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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Pharmacogenet Genomics. Author manuscript; available in PMC 2012 March 1.
Published in final edited form as:
PMCID: PMC3098758

Very important pharmacogene summary: ABCB1 (MDR1, P-glycoprotein)

ABCB1 description

ABCB1 (MDR1) is one of many ubiquitous adenosine triphosphate (ATP)-binding cassette (ABC) genes present in all kingdoms of life that is responsible for cellular homeostasis [13]. ABC genes encode transporter and channel proteins possessing multiple membrane-spanning domains that form a pore, and intracellular nucleotide-binding domains for ATP-dependent translocation of substrates or ions across the cell membrane [1,4,5]. Although bacterial ABC proteins function as both importers and exporters [6], all eukaryotic ABC proteins are efflux pumps [1,7]. ABCB1 is one of 49 putative members in the superfamily of human ABC transporters [8,9] within subfamily B (MDR/TAP), which is one of seven phylogenetically distinct sub-families [4] with overlapping substrate specificity [10] (see Wageningen University website,

Molecular and protein structure

ABCB1 was first cloned by Riordan et al. [11] in 1985. The gene lies less than 25 kb from ABCB4 on chromosome 7q21.12 [UCSC Genome Browser, March 2006 Assembly (hg18)]. Analysis of human cell lines, liver tissue, and lymphocytes consistently show ABCB1 to contain 29 exons in a genomic region spanning 209.6 kb [12] (GenBank accession number NT_007933). Two 5′ exons are untranslated. Two primary transcriptional start regions exist: a proximal promoter in exon 1 and intron 1 for constitutive expression, and a cryptic distal promoter active in drug-selected cell lines and cancer patient samples for overexpression of the protein product. The ABCB1 promoter region contains a few low-frequency polymorphisms and is relatively invariant compared with other genes in the genome [13].

The messenger RNA (mRNA) is 4872 bp in length, including the 5′ untranslated region (RefSeq accession NM_000927.3), which gives rise to a protein that is 1280 amino acids in length, named P-glycoprotein (P-gp) [12]. The secondary structure of P-gp reveals two homologous halves to the protein, each containing six transmembrane domains and a nucleotide-binding domain (see image from Fung et al. [14]). The existence and number of putative splice variants is undetermined [12]. Alternative transcripts for ABCB1 have been predicted from sequence alignments with human complementary DNA (search ABCB1 at in AceView), protein sequences, and expressed sequence tags [15]. P-gp is posttranslationally modified by phosphorylation and N-glycosylation. Differential phosphorylation of P-gp by kinases has been shown to influence P-gp activity [16,17]. A number of mechanistic observations have been made from low-resolution crystal structures for P-gp in bacteria [18] and Chinese hamster ovary cells [2], and from a high-resolution structure of the mouse homolog with 87% sequence identity to humans (see Protein Data Bank accession numbers 3G60, 3G5U, 3G61 at [19]. The 12 transmembrane helices form a toroidal protein with an aqueous pore (see image from Higgins et al.) [2,20]. Two nucleotide-binding domains for the protein lie in the cytoplasm. The pore is lined with hydrophobic and aromatic amino acids at the extracellular-facing half of the pore, whereas the cytosolic-facing portion of the pore contains polar, charged residues [19]. Structural analysis reveals two openings in the protein at the lipid bilayer to permit extraction of substrates directly from the membrane upon their passive diffusion into the cell (see image from Aller et al.) [2,18,19]. Several highly conserved residues within the pore are able to recognize a diverse range of substrates. The protein exhibits high conformational flexibility to allow for structural rearrangements in binding and effluxing substrates [19]. Substrate-bound images reveal the capacity for P-gp to distinguish stereoisomers and simultaneously bind multiple substrates at overlapping binding sites. The ability to bind substrates in close proximity to one another provides a mechanistic rationale for observed functional interactions between coadministered substrates (e.g. allosteric, competitive and noncompetitive inhibition, and cooperativity) [10,21,22].

Tissue distribution and function

P-gp is expressed in a polarized manner in the plasma membrane of cells in barrier and elimination organs, where it has protective and excretory functions [23]. It plays an important role in first-pass elimination of orally administered drugs to limit their bioavailability by effluxing drugs from the lumen-facing epithelia of the small intestine and colon, and from the bile-facing canaliculi of the liver. It eliminates substrates from the systemic circulation at the urine-facing side of the brush border membrane of proximal tubules in the kidney, and again through biliary excretion. It restricts the permeability of drugs into ‘sanctuary’ organs from the apical or serosal side of blood–tissue barriers (e.g. blood–brain, blood–cerebral spinal fluid, blood–placenta, blood–testis barriers) [24]. P-gp expression in the adrenal cortex is thought to play a role in hormone transport and homeostasis, and glucorcorticoid resistance [5,25]. In lymphocytes and other immunological and blood components, P-gp putatively plays a role in viral resistance and in trafficking cytokines and enveloped viruses [5,26]. P-gp is also thought to be important for steroid partitioning and lipid homeostasis in the periphery and central nervous system [25,27,28]. Intracellular P-gp with unknown function has been detected in the endoplasmic reticulum, vesicles, and the nuclear envelope, and has been associated with cell trafficking machinery [29]. Relevant to the clinical challenge of MDR, P-gp is overexpressed in numerous tissues transformed by cancer.

Physiological role

P-gp was discovered in 1970 by Biedler et al. [30] who observed the phenomenon of MDR conferred by a cell surface protein in mammalian cell lines. This membrane protein conferred a 2500-fold increase in drug resistance to actinomycin D and cross-resistance to a single exposure of mithramycin, vinblastine, vincristine, puromycin, daunomycin, demecolcine, and mitomycin C. The 170 kD phosphoglycoprotein, or ‘permeability’ glycoprotein, was identified as the cause for reduced cellular drug exposure [31] by its active extrusion of drugs from the cell [32,33]. The physiological impact of this multidrug efflux pump was appreciated in 1994 by Schinkel et al. [34] who observed a 100-fold increase in the penetration of antiparasitic medication, ivermectin, into the brain of genetically engineered mice lacking abcb1. Animals naturally deficient for abcb1 were also found to exhibit neurological and fetal drug toxicity because of a breach in the blood–brain and blood–placenta barriers in which P-gp is normally active [35,36]. A 4-bp deletion (ABCB1-1 Delta) was subsequently identified as the cause of the nonfunctioning allele in dogs [36], which led to the proposed dosing changes in veterinary medicine [37,38]. In humans, spontaneous deletion of ABCB1 has not been described, but a nonfunctional variant was found in two heterozygous individuals in which a single nucleotide polymorphism (SNP), T3587G, results in an isoleucine to serine change at residue 1196 in the second ATP-binding domain of P-gp [39]. However, in one heterozygous subject the SNP was not shown to affect the clearance of the P-gp substrate, SN-38, after parenteral irinotecan administration [39,40]. The frequency of the 3587G allele was 1 : 300 in a Japanese population; therefore, homozygotes with two copies of the nonfunctioning 1196Ser allele would be very rare (1 : 100 000).

Numerous common coding variants in ABCB1 have been studied for their potential influence on P-gp expression, function, and disease risk. Genetic associations with molecular or clinical phenotypes have largely been inconsistent (see ABCB1 genetics) [4143]. As a result, no adjustments in drug dosing have been recommended for individuals carrying sequence variants of ABCB1 in humans, and replication studies are needed to understand the influence of ABCB1 genetics on disease susceptibility. Current clinical considerations for P-gp are therefore related to its important role in (i) MDR and (ii) drug–drug interactions, derived primarily from its broad substrate specificity and variable intrinsic and drug-induced expression [44].

Compounds that interact with P-gp

P-gp recognizes and effluxes a multitude of structurally and biochemically unrelated substrates (cyclic, linear, basic, uncharged, zwitterionic, negatively charged, hydrophobic, aromatic, nonaromatic, amphipathic) from 250 to 4000 molecular weight [10,29,45], sufficiently indeterminate to predict in drug design [7]. Substrates include xenobiotics, endogenous compounds [e.g. peptides (including β-amyloids), steroid hormones, lipids, phospholipids, cholesterol, and cytokines] [22], pharmaceuticals [46], neutraceuticals (e.g. St John’s wort), dietary compounds (e.g. grapefruit juice, green tea) [47,48], and other compounds, which may also modulate P-gp activity [49] (Table 1). P-gp compounds can act as substrates, inhibitors, inducers, and repressors; and citations refer to P-gp compounds as being in more than one category, depending on the circumstance [10]. Modulation of ABCB1 gene expression and/or P-gp activity by various mechanisms consequently influences P-gp-mediated drug disposition.

Table 1
Compounds that interact with P-glycoprotein

Repressors of P-gp, including certain antineoplastic agents that act at nuclear receptors [73], or endotoxin [74], cobalamin [50], and atorvastatin [75,76], potentiate the action of substrates; whereas rifampin (rifampicin) [51] and cell stress signals induce P-gp-mediated drug resistance [29,50,75]. Another mechanism for P-gp-related pharmacoresistance to cytotoxic agents is hypothesized to relate to the cell stress signals they induce [52,77]. Upregulation of ABCB1 gene expression can occur at gene promoter sequences through transactivation [10,47,78], for example, by the pregnane X receptor (NR1I2) gene in response to substrates that may have overlapping specificity for P-gp [29]; or induction can occur independent of nuclear receptors [79]. Alternatively, epigenetic inactivation of P-gp can occur by DNA methylation at specific nucleotide sequences within the promoter sequence, called CpG islands, as has been observed in some cancer tissues [80]; or downregulation of P-gp can also occur by mechanisms other than by DNA methylation, for example, in response to cobalamin, a vitamin B-12 derivative [50].

Drug interactions

Many studies have characterized the interactions among P-gp compounds, as concomitant administration can substantially alter the pharmacokinetics of the compounds involved [81]. Research has focused on both the deleterious and beneficial effects of interactions among P-gp compounds: (i) interactions that potentially affect drug safety and efficacy [22], and (ii) interactions exploited to optimize drug delivery (see MDR).

Drug safety and efficacy are major health concerns, particulary for drugs with a narrow therapeutic index and/or large clinical effect [82]. A number of drug interactions of clinical relevance are cited as warnings in the drug labels by the Federal Drug Administration. For example, the drug label for the contraceptive, Trinessa (Watson Pharma, Inc.), warns against potential drug inefficacy when coadministered with compounds that induce P-gp (e.g. rifampin, St John’s wort, protease inhibitors, carbamazepine, and barbiturates). The drug label for the antidiarrheal, loperamide (Imodium, McNeil Consumer Healthcare), warns against neurotoxic side effects when coadministered with P-gp inhibitors (e.g. quinidine, ritonavir) as this gut-targeted optiate relies upon P-gp to prohibit intestinal absorption and entry into the central nervous system [83].

Interactions between compounds are substrate-specific, concentration-dependent [22], and tissue-specific [84]. For example, unlike the drug-potentiating interaction between quinine [85,86] or ritonavir [87] on loperamide, the potent P-gp inhibitor, tariquidar, does not produce the same analgesic effects, despite its efficient inhibition of P-gp in lymphocytes. This is presumably because of tissue-specific factors [84]. Concentration is another important determinant of drug interactions. For example, at the therapeutic concentration for the β blocker and P-gp substrate, propranolol (Innopran Xl, Reliant Pharmaceuticals Inc.), modulation of P-gp by other compounds does not affect propranolol disposition. Other influences include key pharmacokinetic genes that affect the disposition of substrates for P-gp. For example, P-gp and cytochrome P450 3A4 metabolizing enzyme (CYP3A4) overlap in tissue distribution and specificity for a substantial number of substrates, inducers, and inhibitors [88]. Furthermore, genes responsible for the disposition of a drug can act synergistically [89]. Marchetti et al. cite clinically relevant drug interactions influenced by the interplay of ABCB1 with other genes in the disposition of P-gp compounds, such as paclitaxel and cyclosporine A (CsA) (through CYP3A4 inhibition), digoxin and rifampin (through CYP3A4 induction), and topotecan and elacridar (through ABCG2 inhibition) [90].

Multi-drug resistance

Drug resistance by multiple mechanisms [46,52,9193] accounts for more than 90% treatment failure in metastatic cancer [92,94]. MDR from intrinsic (drug-naive) and acquired (drug-induced) overexpression of P-gp [93] is a notable impediment to brain-targeted therapies (e.g. antiepileptics, neuroantiretrovirals) and chemotherapies [7,73,95,96]. P-gp expression is predictive of between 30 and 40% of treatment failure in epilepsy [5,47,97] and is correlated with drug nonresponse in acute myeloid leukemia [98], childhood neuroblastoma [99] and sarcoma [100], and other cancers [101]. The relationship between P-gp expression with nonresponse to chemotherapy and drug-induced upregulation of P-gp according to tumor type is reviewed nicely by Takara et al. [46].

Known interactions between substrates and modulators of P-gp have been exploited in drug development and treatment protocols to overcome low drug delivery. Inhibitors of P-gp, such as formulary excipients [e.g. tocopherol (vitamin E preparation, TPGS 1000) and Cremophor EL] [5355] and approved drugs, are clinically used to enhance the delivery of P-gp substrates. Verapamil and CsA are examples of the first-generation of ‘P-gp reversal agents’ [46] used in combination with antineoplastic agents, such as doxorubicin, vincristine, and paclitaxel to enhance bioavailability [102106]. However, dose-limiting toxicity of early reversal agents and formulary excipients has led to the development of second-generation antagonists of P-gp, such as valspodar (PSC833), with ten-fold greater potency for P-gp and less side effects [91,107,108].

Substrate interactions with other pharmacokinetic genes affecting the absorption, distribution, metabolism, elimination (ADME) of drugs play a significant role in the effectiveness of P-gp reversal agents. Substrate specificity for multiple ADME genes can be advantageous or disadvantageous in adjunct therapy. For example, the mechanism by which both CsA and valspodar enhance the bioavailability of paclitaxel is owed in part to their inhibition of CYP3A4 [109,110], ABCC2 [111], and other elimination-pathway genes (e.g. CYP2J2) [112] for paclitaxel. In contrast, nonspecific inhibition of multiple elimination-pathway genes involved in drug clearance can lead to side effects associated with the prolonged half life of the primary drug. As more is known about the gene expression profile of specific pathological conditions, P-gp reversal agent use can be optimized. For example, where redundant drug resistance mechanisms are operant, as with ABCB1, ABCC1 (MRP1) and ABCG2 (BCRP) in acute myeloid leukemia [52,113], inhibition of multiple MDR genes can be beneficial. Characterization of the genes responsible for pharmacoresistance in a particular disease or disease stage is used to inform drug treatment (see P-gp-guided therapy). Also, third-generation P-gp reversal agents [e.g. tariquidar (XR9576), zosuquidar (LY335979), laniquidar (R101933), and ONT-093 (OC-144-093)] with greater specificity for Pgp and less affinity for other ADME genes have been developed [91,114]. A number of the newer-generation Pgp reversal agents [e.g. tariquidar, valspodar, zosuquidar, ONT-093, elacridar (GF120918, GG918), and CBT-1] has shown promise in in vitro and early trials for epilepsy and cancer treatments [91,96,115117].

P-gp-guided therapy

Techniques to characterize the mechanisms of drug resistance that are operant in individual patients inform treatment with P-gp antagonists as adjuncts in the appropriate case. Single photon emission computed tomography analysis of the P-gp substrate, 99mTc sestamibi, is used to probe P-gp-positive cells as a way to predict pharmacoresistance to antiepileptic [96] and antitumor drugs [118,119]. This technique is shown to be a cost-effective method for pre-selecting responders to lung cancer treatment [56]. 99mTc sestamibi is also used to monitor the efficacy of P-gp reversal agents in sensitizing pharmacoresistant cells to P-gp substrates [120]. A phase I clinical trial using vinblastine and valspodar reversal agent, and 99mTc sestamibi imaging to monitor the sensitization of P-gp-positive cells, showed increased 99mTc sestamibi retention in tumor cells of metastatic renal carcinoma patients (and therefore presumably, cytotoxic agent, vinblastine) [118]. Tariquidar/taxane/anthracycline polytherapy guided by serial 99mTc sestamibi tumor scans is currently in a phase II clinical trial for breast cancer with acquired pharmacoresistance (search Clinical trial ID: NCT00048633 at Results to date show that cancers exhibiting de novo pharmacoresistance (drug naive), such as leukemias, myelomas, lymphomas, and breast and ovarian cancers, are most amenable to P-gp modulation with reversal agents as adjunct therapy.

ABCB1 genetics

Disease-causing mutations in 14 of the ABC superfamily members have been described, as in CFTR (ABCC7) for cystic fibrosis, ABCA4 for macular degeneration, ABCC2 and ABCB11 for biliary dysfunction, and ABCA1, ABCG5, ABCG8, and ABCD1 for fatty acid/lipid disorders [4]. A large corpus of the literature about sequence variations for ABCB1 exists, however there is no clear consensus regarding the contribution of ABCB1 variation to disease risk [41,121,122]; and despite evidence for interindividual variability in ABCB1 expression and function [14,123,124], the genetic contribution is unclear [41]. A great number of studies have been carried out to establish the role of ABCB1 genetics in various phenotypes such as P-gp expression, function, drug response, and disease susceptibility with little consensus. Here we limit mentioning to genotype–phenotype associations that are substantiated by study replication, meaningful sample size, and appropriate multitesting correction. See Leschziner et al. [41] for a detailed review of the controversial literature regarding genetic association of ABCB1 SNPs and haplotypes with P-gp expression, activity, drug response, and disease risk.

As of 30 April 2009 for build 130 of the Single Nucleotide Polymorphism database (dbSNP) [14], there are 1279 SNPs in the ABCB1 gene region, 62 of which are coding (22 synonymous, 41 nonsynonymous, and one in the start codon). The number and frequency of SNPs observed varies by ethnicity. Excluding SNPs below 5% allele frequency, there are approximately 124 SNPs observed in Caucasians, 134 in African–Americans, 153 in Chinese, and 166 in Japanese (see HapMap release 27 at Additional information is available at the University of California, San Francisco Pharmacogenetics of Membrane Transporters Database (

About 2.6 times fewer (n=4) SNPs occur in the transmembrane domains compared with the intracellular and extracellular regions of the protein. None of the 3 untranslated region SNPs are reported to alter mRNA stability [14]. The three most common SNPs in the protein coding region are rs1128503 (1236T > C, Gly412Gly), rs2032582 (2677T>G/A, Ser893Ala/Thr), and rs1045642 (3435T > C, Ile1145Ile) [125], according to the National Center for Biotechnology Information build 130 of dbSNP. These three SNPs have been the focus of many pharmacokinetic and disease association studies with controversial results [41].

Common coding SNPs

Rs1128503 (1236T>C, mRNA 1654T>C, Gly412Gly)

According to dbSNP, the C allele of the synonymous (Gly412Gly) SNP, rs1128503 (1236T>C), ranges in allele frequency from 30 to 93% depending upon the ethnic population, with C being the minor allele in Asians, and T being the minor allele in Africans. Although many studies have undertaken characterizing potential phenotypic associations for this silent SNP, the literature bears no consensus [41]. As a brief illustration, studies found increased drug exposure or drug response associated with the 1236 CC genotype [126], the 1236 TT genotype [127,128], or no genetic effect was found with regard to rs1128503 [129].

Rs2032582 (2677T>G/A, mRNA 3095T>G/A, Ser893Ala/Thr)

The triallelic SNP, rs2032582 (2677T > G/A, Ser893Ala/ Thr), has been well studied because it is a common amino acid change in P-gp. The 893 serine-bearing 2677T allele frequency varies as much as 2–65% among world populations, according to data from the International HapMap project ( The frequency of 893Ala/Ala homozygotes (2677 GG genotype) is greater than 81% in African populations, compared with 10–32% in American Indians, Mexicans, Italians, Asians, and Caucasians. According to dbSNP, the 893 threonine-bearing 2677A allele is relatively uncommon [130,131], ranging from 0 to 17% in different ethnic populations.

Despite a large number of studies testing potential phenotypic associations with this nonsynonymous SNP, the literature is inconclusive [41,57,132]. To illustrate briefly, evidence exists in favor of [133,134] and against [135,136] the association of the 893Ser allele with altered P-gp activity and expression [41]; 893Ser has been associated with an increase [127,131], decrease [133], and no change [129,137141] in drug exposure and drug effect [41]. Studies for clinical outcome and disease risk are similarly discordant [41]. As a brief example, research in drug treatment and disease risk for the related conditions of inflammatory bowel disease, Crohn’s disease, and ulcerative colitis has implicated the 893Ala allele [142], the 893Ser/Ser genotype [143], and has shown no genotypic effect with regard to rs2032582 [144,145].

Rs1045642 (3435T>C, mRNA 3853T>C, Ile1145Ile)

The synonymous SNP, rs1045642 (3435T>C), exhibits larger interethnic allele frequency differences, with the 3435C allele ranging between 34 and 90% across populations [57,58,132]. In 2000, a study by Hoffmeyer et al. [146] implicated the 3435T allele with altered P-gp function, showing association of the 3435 TT genotype with low expression of P-gp in the gut and increased plasma levels of digoxin relative to the 3435 CC genotype. This finding generated much interest in this silent mutation with regard to P-gp expression and activity; however, replication studies have not borne out this and many other phenotypic associations [41]. To illustrate briefly, studies have associated the 3435 TT genotype with decreased [125,147149] and increased [58] expression of P-gp, and no genotypic effect [135]. Likewise, studies have shown increased drug exposure associated with the 3435T allele or TT genotype [150152], the 3435 CC genotype [148,153,154], and no genetic effect with regard to rs1045642 [137,140,141,152,155158]. Association studies for clinical outcomes are similarly inconclusive. Briefly, there is evidence for [159,160] and against [161] the association of 3435 CC with drug response in epilepsy, and no genetic effect with regard to rs1045642 [162,163].

ABCB1 haplotypes

Closely positioned sequence variants tend not to segregate independently with each generation because of linkage disequilibrium (LD). As a result, multiple variant alleles are inherited together on the same physical chromatid in a particular pattern. That is to say that for linked variant alleles, the occurrence of one variant allele informs the valence of other alleles with a given predictability. For example, the three most common coding SNPs at nucleotides 1236, 2677, and 3435 are in high LD [15] and are observed most frequently as either the 893Ala-containing CGC haplotype or 893Ser-containing TTT haplotype in most ethnic groups [133,139,164]. Other observed haplotypes extend beyond the exonic region of ABCB1 [165]. Leschziner et al. [15] observed LD extending 75 kb, linking 3′ variant alleles of ABCB1 to coding variant alleles of the adjacent ABC transporter gene, ABCB4.

Haplotype structure relates to the location of recombination hot spots and ancestry-specific patterns of LD [165,166]. Tang et al. [164] observed ethnic-specific LD blocks at the ABCB1 locus that are 80, 60, and 40 kb in length and distinguish Chinese, Malay, and Indian populations, respectively. Similarly, comparison of the mutation rate between Beninese Africans (one variant per 224 bp) and African–Americans (one variant per 172 bp) reflects an admixture in the US cohort that differentiates the ABCB1 haplotype structure in these populations [167]. Accordingly, haplotype frequencies differ by ethnic group. For example, the 893Ser-containing TTT haplotype occurs approximately 2–5-fold less often in African– Americans [133,139] than in Caucasians [133,139] and Asians [164].

A haplotype by definition is not bound by a gene region, but gene-specific haplotypes can acquire allelic designations in the literature. Sequence analysis of ABCB1 in different ethnic groups has been performed [15,40,133,139,164,167,168] and led to the designation of ‘star alleles’ [40,133,139], as explained by Robarge et al. [169]. Briefly, the designation of ABCB1 star alleles follows rules established by the Cytochrome P450 Allele Nomenclature Committee and others for naming haplotypes observed for cytochrome P450, uridinediphosphate-glucuronosyltransferase, N-acetyltransferase, and aldehyde dehydrogenase [169,170] genes. Star alleles are defined relative to an arbitrarily established reference sequence, denoted as *1. ABCB1*1 contains 1236C, 2677G (893Ala), and 3435C. Many star allele designations for ABCB1 are currently not harmonized in the literature. To illustrate briefly, ABCB1*2, as defined by Kim et al. [133], harbors three coding variants, namely 1236T, 2677T (893Ser), and 3435T; whereas ABCB1*2, as named by Kroetz et al. [139], contains 3435T [and is a reference for 1236C and 2677G (893Ala)]. ABCB1*13 per Kroetz et al. [139] [1236T, 2677T (893Ser), 3435T, and three intronic SNPs] is most similar to ABCB1*2 defined by Kim et al. [133] as they are indistinguishable in terms of the coding region and amino acid sequence.

The vast majority of haplotype studies for ABCB1 do not take into account all segregating sites that are used to distinguish ABCB1 star alleles, but interrogate a select few variants. Genotyping the three most common ABCB1 SNPs at 1236, 2677, and 3435 captures a large portion of observed population haplotypes [133,139,171]. Haplotype association studies for ABCB1 have been inconclusive [41]. To illustrate briefly, the 893Ser-bearing TTT (1236, 2677, 3435) haplotype was associated with increased irinotecan levels [40], but enhanced fexofenadine elimination [133] and increased pharmacoresistance to antiepileptic treatment was associated with homozygous 893-Ala-bearing CGC/CGC individuals in one study [172], but with CGC and 893Ser-bearing TTT haplotypes in another study [173]. However, worth mention is the replication of an association between the 893Ser-bearing TTT (1236, 2677, 3435) haplotype and increased digoxin exposure in 195 Europeans [174] and in a small study of 12 Chinese [175].

To investigate the regulatory impact of promoter variants on functional phenotypes, haplotype analysis of the promoter region has also been performed [13,149,171,176]. Wang et al. [13] observed a haplotype formed from eight low-frequency variants (< 5% minor allele frequency) in the promoter region that accounted for 85% of all haplotypes observed in five ethnic groups. They functionally characterized promoter haplotypes observed in Chinese, Malays, Indians, European Americans, and African–Americans using an in-vitro reporter assay and found significant ethnic-specific differences in promoter activity, although activity differed by the cell line used in the assay (presumably because of cell-specific regulatory factors). Other work has been done to understand the relationship between regulatory and coding variants for ABCB1 and their potential association with endo-phenotypes. Takane et al. [149] showed that variation in promoter haplotype activity was independent of variation at the synonymous 3435 SNP, and the methylation status of the proximal promoter did not correlate with ABCB1 mRNA expression. Jiang et al. [171] found an association between the promoter methylation status and variation in coding SNPs for ABCB1. They showed that lower promoter methylation was associated with the 3435 TT and 893Ala-containing 2677 genotypes, whereas the 893Ser-containing TTT (1236, 2677, 3435) haplotype was associated with higher methylation. More research is needed to elucidate the functional relevance of regulatory variants for ABCB1 and their potential value to predicting P-gp-related phenotypes.

Despite much work to ascertain the genetic contribution of ABCB1 on drug disposition and disease susceptibility, the accumulation of studies to date are unclear. Until data are amassed to form a consensus about the role of genetics in P-gp-related phenotypes, the primary clinical focus on P-gp relates to its role in (i) MDR and (ii) drug–drug interactions [44].

Additional information is presented at the Pharmacogenomics Knowledge Base (PharmGKB) website ( in a search for ABCB1, accession number PA267, and at


PharmGKB is supported by the NIH/NIGMS Pharmaco-genetics Research Network (PGRN; UO1GM61374).


1. Jones PM, George AM. The ABC transporter structure and mechanism: perspectives on recent research. Cell Mol Life Sci. 2004;61:682–699. [PubMed]
2. Rosenberg MF, Callaghan R, Ford RC, Higgins CF. Structure of the multidrug resistance P-glycoprotein to 2.5 nm resolution determined by electron microscopy and image analysis. J Biol Chem. 1997;272:10685–10694. [PubMed]
3. Croop JM. P-glycoprotein structure and evolutionary homologies. Cytotechnology. 1993;12:1–32. [PubMed]
4. Borst P, Elferink RO. Mammalian ABC transporters in health and disease. Annu Rev Biochem. 2002;71:537–592. [PubMed]
5. Ambudkar SV, Dey S, Hrycyna CA, Ramachandra M, Pastan I, Gottesman MM. Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annu Rev Pharmacol Toxicol. 1999;39:361–398. [PubMed]
6. Chang G. Multidrug resistance ABC transporters. FEBS Lett. 2003;555:102–105. [PubMed]
7. Löscher W, Potschka H. Role of multidrug transporters in pharmacoresistance to antiepileptic drugs. J Pharmacol Exp Ther. 2002;301:7–14. [PubMed]
8. McGuire AH, Dehdashti F, Siegel BA, Lyss AP, Brodack JW, Mathias CJ, et al. Positron tomographic assessment of 16 alpha-[18F] fluoro-17 betaestradiol uptake in metastatic breast carcinoma. J Nucl Med. 1991;32:1526–1531. [PubMed]
9. Sharom FJ. ABC multidrug transporters: structure, function and role in chemoresistance. Pharmacogenomics. 2008;9:105–127. [PubMed]
10. Zhou SF. Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition. Xenobiotica. 2008;38:802–832. [PubMed]
11. Riordan JR, Deuchars K, Kartner N, Alon N, Trent J, Ling V. Amplification of P-glycoprotein genes in multidrug-resistant mammalian cell lines. Nature. 1985;316:817–819. [PubMed]
12. Bodor M, Kelly EJ, Ho RJ. Characterization of the human MDR1 gene. Aaps J. 2005;7:E1–E5. [PMC free article] [PubMed]
13. Wang B, Ngoi S, Wang J, Chong SS, Lee CG. The promoter region of the MDR1 gene is largely invariant, but different single nucleotide polymorphism haplotypes affect MDR1 promoter activity differently in different cell lines. Mol Pharmacol. 2006;70:267–276. [PubMed]
14. Fung KL, Gottesman MM. A synonymous polymorphism in a common MDR1 (ABCB1) haplotype shapes protein function. Biochim Biophys Acta. 2009;1794:860–871. [PMC free article] [PubMed]
15. Leschziner G, Zabaneh D, Pirmohamed M, Owen A, Rogers J, Coffey AJ, et al. Exon sequencing and high resolution haplotype analysis of ABC transporter genes implicated in drug resistance. Pharmacogenet Genomics. 2006;16:439–450. [PubMed]
16. Lelong-Rebel IH, Cardarelli CO. Differential phosphorylation patterns of P-glycoprotein reconstituted into a proteoliposome system: insight into additional unconventional phosphorylation sites. Anticancer Res. 2005;25:3925–3935. [PubMed]
17. Idriss HT, Hannun YA, Boulpaep E, Basavappa S. Regulation of volume-activated chloride channels by P-glycoprotein: phosphorylation has the final say! J Physiol. 2000;524(Pt 3):629–636. [PubMed]
18. Seigneuret M, Garnier-Suillerot A. A structural model for the open conformation of the mdr1 P-glycoprotein based on the MsbA crystal structure. J Biol Chem. 2003;278:30115–30124. [PubMed]
19. Aller SG, Yu J, Ward A, Weng Y, Chittaboina S, Zhuo R, et al. Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science. 2009;323:1718–1722. [PMC free article] [PubMed]
20. Higgins CF. Multiple molecular mechanisms for multidrug resistance transporters. Nature. 2007;446:749–757. [PubMed]
21. Sheps JA. Biochemistry. Through a mirror, differently. Science. 2009;323:1679–1680. [PubMed]
22. Litman T, Zeuthen T, Skovsgaard T, Stein WD. Competitive, non-competitive and cooperative interactions between substrates of P-glycoprotein as measured by its ATPase activity. Biochim Biophys Acta. 1997;1361:169–176. [PubMed]
23. Brinkmann U, Eichelbaum M. Polymorphisms in the ABC drug transporter gene MDR1. Pharmacogenomics J. 2001;1:59–64. [PubMed]
24. Fromm MF. Importance of P-glycoprotein at blood-tissue barriers. Trends Pharmacol Sci. 2004;25:423–429. [PubMed]
25. Meijer OC, Karssen AM, de Kloet ER. Cell- and tissue-specific effects of corticosteroids in relation to glucocorticoid resistance: examples from the brain. J Endocrinol. 2003;178:13–18. [PubMed]
26. Raviv Y, Puri A, Blumenthal R. P-glycoprotein-overexpressing multidrug-resistant cells are resistant to infection by enveloped viruses that enter via the plasma membrane. FASEB J. 2000;14:511–515. [PubMed]
27. Jeannesson E, Siest G, Bastien B, Albertini L, Aslanidis C, Schmitz G, Visvikis-Siest S. Association of ABCB1 gene polymorphisms with plasma lipid and apolipoprotein concentrations in the STANISLAS cohort. Clin Chim Acta. 2009;403:198–202. [PubMed]
28. Karssen AM, Meijer OC, van der Sandt IC, De Boer AG, De Lange EC, De Kloet ER. The role of the efflux transporter P-glycoprotein in brain penetration of prednisolone. J Endocrinol. 2002;175:251–260. [PubMed]
29. Miller DS, Bauer B, Hartz AM. Modulation of P-glycoprotein at the blood-brain barrier: opportunities to improve central nervous system pharmacotherapy. Pharmacol Rev. 2008;60:196–209. [PMC free article] [PubMed]
30. Biedler JL, Riehm H. Cellular resistance to actinomycin D in Chinese hamster cells in vitro: cross-resistance, radioautographic, and cytogenetic studies. Cancer Res. 1970;30:1174–1184. [PubMed]
31. Juliano RL, Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta. 1976;455:152–162. [PubMed]
32. Gottesman MM, Pastan I. The multidrug transporter, a double-edged sword. J Biol Chem. 1988;263:12163–12166. [PubMed]
33. Ling V. Drug resistance and membrane alteration in mutants of mammalian cells. Can J Genet Cytol. 1975;17:503–515. [PubMed]
34. Schinkel AH, Smit JJ, van Tellingen O, Beijnen JH, Wagenaar E, van Deemter L, et al. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell. 1994;77:491–502. [PubMed]
35. Umbenhauer DR, Lankas GR, Pippert TR, Wise LD, Cartwright ME, Hall SJ, Beare CM. Identification of a P-glycoprotein-deficient subpopulation in the CF-1 mouse strain using a restriction fragment length polymorphism. Toxicol Appl Pharmacol. 1997;146:88–94. [PubMed]
36. Barbet JL, Snook T, Gay JM, Mealey KL. ABCB1-1 Delta (MDR1-1 Delta) genotype is associated with adverse reactions in dogs treated with milbemycin oxime for generalized demodicosis. Vet Dermatol. 2009;20:111–114. [PubMed]
37. Mueller RS, Bettenay SV. A proposed new therapeutic protocol for the treatment of canine mange with ivermectin. J Am Anim Hosp Assoc. 1999;35:77–80. [PubMed]
38. Merola V, Khan S, Gwaltney-Brant S. Ivermectin toxicosis in dogs: a retrospective study. J Am Anim Hosp Assoc. 2009;45:106–111. [PubMed]
39. Mutoh K, Mitsuhashi J, Kimura Y, Tsukahara S, Ishikawa E, Sai K, et al. A T3587G germ-line mutation of the MDR1 gene encodes a nonfunctional P-glycoprotein. Mol Cancer Ther. 2006;5:877–884. [PubMed]
40. Sai K, Kaniwa N, Itoda M, Saito Y, Hasegawa R, Komamura K, et al. Haplotype analysis of ABCB1/MDR1 blocks in a Japanese population reveals genotype-dependent renal clearance of irinotecan. Pharmacogenetics. 2003;13:741–757. [PubMed]
41. Leschziner GD, Andrew T, Pirmohamed M, Johnson MR. ABCB1 genotype and PGP expression, function and therapeutic drug response: a critical review and recommendations for future research. Pharmacogenomics J. 2007;7:154–179. [PubMed]
42. Fromm MF. The influence of MDR1 polymorphisms on P-glycoprotein expression and function in humans. Adv Drug Deliv Rev. 2002;54:1295–1310. [PubMed]
43. Marzolini C, Paus E, Buclin T, Kim RB. Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther. 2004;75:13–33. [PubMed]
44. Aszalos A. Drug-drug interactions affected by the transporter protein, P-glycoprotein (ABCB1, MDR1) II. Clinical aspects. Drug Discov Today. 2007;12:838–843. [PubMed]
45. Kerns EH, Di L. Drug-like properties: concepts, structure design and methods: from ADME to toxicity optimization. Burlington, MA, USA: Elsevier Inc; 2008.
46. Takara K, Sakaeda T, Okumura K. An update on overcoming MDR1-mediated multidrug resistance in cancer chemotherapy. Curr Pharm Des. 2006;12:273–286. [PubMed]
47. Zhou S, Lim LY, Chowbay B. Herbal modulation of P-glycoprotein. Drug Metab Rev. 2004;36:57–104. [PubMed]
48. Tracy TS, Kingston RL. Herbal products, toxicology and clinical pharmacology. 2nd ed. Totowa, New Jersey, USA: Humana Press Inc; 2007.
49. Zhang W, Han Y, Lim SL, Lim LY. Dietary regulation of P-gp function and expression. Expert Opin Drug Metab Toxicol. 2009;5:789–801. [PubMed]
50. Marguerite V, Beri-Dexheimer M, Ortiou S, Gueant JL, Merten M. Cobalamin potentiates vinblastine cytotoxicity through downregulation of mdr-1 gene expression in HepG2 cells. Cell Physiol Biochem. 2007;20:967–976. [PubMed]
51. Greiner B, Eichelbaum M, Fritz P, Kreichgauer HP, von Richter O, Zundler J, Kroemer HK. The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin. J Clin Invest. 1999;104:147–153. [PMC free article] [PubMed]
52. Kuo MT. Redox regulation of multidrug resistance in cancer chemotherapy: molecular mechanisms and therapeutic opportunities. Antioxid Redox Signal. 2009;11:99–133. [PubMed]
53. Collnot EM, Baldes C, Wempe MF, Kappl R, Huttermann J, Hyatt JA, et al. Mechanism of inhibition of P-glycoprotein mediated efflux by vitamin E TPGS: influence on ATPase activity and membrane fluidity. Mol Pharm. 2007;4:465–474. [PubMed]
54. Theis JG, Chan HS, Greenberg ML, Malkin D, Karaskov V, Moncica I, et al. Increased systemic toxicity of sarcoma chemotherapy due to combination with the P-glycoprotein inhibitor cyclosporin. Int J Clin Pharmacol Ther. 1998;36:61–64. [PubMed]
55. Ross DD, Wooten PJ, Tong Y, Cornblatt B, Levy C, Sridhara R, et al. Synergistic reversal of multidrug-resistance phenotype in acute myeloid leukemia cells by cyclosporin A and cremophor EL. Blood. 1994;83:1337–1347. [PubMed]
56. Mohan HK, Miles KA. Cost-effectiveness of 99mTc-sestamibi in predicting response to chemotherapy in patients with lung cancer: systematic review and meta-analysis. J Nucl Med. 2009;50:376–381. [PubMed]
57. Schwab M, Eichelbaum M, Fromm MF. Genetic polymorphisms of the human MDR1 drug transporter. Annu Rev Pharmacol Toxicol. 2003;43:285–307. [PubMed]
58. Dey S. Single nucleotide polymorphisms in human P-glycoprotein: its impact on drug delivery and disposition. Expert Opin Drug Deliv. 2006;3:23–35. [PubMed]
59. Taubert D, von Beckerath N, Grimberg G, Lazar A, Jung N, Goeser T, et al. Impact of P-glycoprotein on clopidogrel absorption. Clin Pharmacol Ther. 2006;80:486–501. [PubMed]
60. Luna-Tortos C, Fedrowitz M, Loscher W. Several major antiepileptic drugs are substrates for human P-glycoprotein. Neuropharmacology. 2008;55:1364–1375. [PubMed]
61. van Helvoort A, Smith AJ, Sprong H, Fritzsche I, Schinkel AH, Borst P, van Meer G. MDR1 P-glycoprotein is a lipid translocase of broad specificity, while MDR3 P-glycoprotein specifically translocates phosphatidylcholine. Cell. 1996;87:507–517. [PubMed]
62. Nikisch G, Eap CB, Baumann P. Citalopram enantiomers in plasma and cerebrospinal fluid of ABCB1 genotyped depressive patients and clinical response: a pilot study. Pharmacol Res. 2008;58:344–347. [PubMed]
63. Uhr M, Tontsch A, Namendorf C, Ripke S, Lucae S, Ising M, et al. Polymorphisms in the drug transporter gene ABCB1 predict antidepressant treatment response in depression. Neuron. 2008;57:203–209. [PubMed]
64. Hauswald S, Duque-Afonso J, Wagner MM, Schertl FM, Lubbert M, Peschel C, et al. Histone deacetylase inhibitors induce a very broad, pleiotropic anticancer drug resistance phenotype in acute myeloid leukemia cells by modulation of multiple ABC transporter genes. Clin Cancer Res. 2009;15:3705–3715. [PubMed]
65. Weiss J, Herzog M, Konig S, Storch CH, Ketabi-Kiyanvash N, Haefeli WE. Induction of multiple drug transporters by efavirenz. J Pharmacol Sci. 2009;109:242–250. [PubMed]
66. Leggas M, Panetta JC, Zhuang Y, Schuetz JD, Johnston B, Bai F, et al. Gefitinib modulates the function of multiple ATP-binding cassette transporters in vivo. Cancer Res. 2006;66:4802–4807. [PubMed]
67. Ehrhardt M, Lindenmaier H, Burhenne J, Haefeli WE, Weiss J. Influence of lipid lowering fibrates on P-glycoprotein activity in vitro. Biochem Pharmacol. 2004;67:285–292. [PubMed]
68. Fox E, Bates SE. Tariquidar (XR9576): a P-glycoprotein drug efflux pump inhibitor. Expert Rev Anticancer Ther. 2007;7:447–459. [PubMed]
69. Pauli-Magnus C, Rekersbrink S, Klotz U, Fromm MF. Interaction of omeprazole, lansoprazole and pantoprazole with P-glycoprotein. Naunyn Schmiedebergs Arch Pharmacol. 2001;364:551–557. [PubMed]
70. Szabo D, Szabo G, Jr, Ocsovszki I, Aszalos A, Molnar J. Anti-psychotic drugs reverse multidrug resistance of tumor cell lines and human AML cells ex-vivo. Cancer Lett. 1999;139:115–119. [PubMed]
71. Hochman JH, Pudvah N, Qiu J, Yamazaki M, Tang C, Lin JH, Prueksaritanont T. Interactions of human P-glycoprotein with simvastatin, simvastatin acid, and atorvastatin. Pharm Res. 2004;21:1686–1691. [PubMed]
72. Kuhne A, Tzvetkov MV, Hagos Y, Lage H, Burckhardt G, Brockmoller J. Influx and efflux transport as determinants of melphalan cytotoxicity: resistance to melphalan in MDR1 overexpressing tumor cell lines. Biochem Pharmacol. 2009;78:45–53. [PubMed]
73. Hermann DM, Kilic E, Spudich A, Kramer SD, Wunderli-Allenspach H, Bassetti CL. Role of drug efflux carriers in the healthy and diseased brain. Ann Neurol. 2006;60:489–498. [PubMed]
74. Kalitsky-Szirtes J, Shayeganpour A, Brocks DR, Piquette-Miller M. Suppression of drug-metabolizing enzymes and efflux transporters in the intestine of endotoxin-treated rats. Drug Metab Dispos. 2004;32:20–27. [PubMed]
75. Callaghan R, Crowley E, Potter S, Kerr ID. P-glycoprotein: so many ways to turn it on. J Clin Pharmacol. 2008;48:365–378. [PubMed]
76. Rodrigues AC, Curi R, Genvigir FD, Hirata MH, Hirata RD. The expression of efflux and uptake transporters are regulated by statins in Caco-2 and HepG2 cells. Acta Pharmacol Sin. 2009;30:956–964. [PubMed]
77. Male DK. Expression and induction of p-glycoprotein-1 on cultured human brain endothelium. J Cereb Blood Flow Metab. 2009;29:1760–1763. [PubMed]
78. Tachibana S, Yoshinari K, Chikada T, Toriyabe T, Nagata K, Yamazoe Y. Involvement of Vitamin D receptor in the intestinal induction of human ABCB1. Drug Metab Dispos. 2009;37:1604–1610. [PubMed]
79. Mitin T, Von Moltke LL, Court MH, Greenblatt DJ. Levothyroxine up-regulates P-glycoprotein independent of the pregnane X receptor. Drug Metab Dispos. 2004;32:779–782. [PubMed]
80. Baker EK, El-Osta A. MDR1, chemotherapy and chromatin remodeling. Cancer Biol Ther. 2004;3:819–824. [PubMed]
81. Aszalos A. Drug-drug interactions affected by the transporter protein, P-glycoprotein (ABCB1, MDR1) I. Preclinical aspects. Drug Discov Today. 2007;12:833–837. [PubMed]
82. Yang XX, Hu ZP, Duan W, Zhu YZ, Zhou SF. Drug-herb interactions: eliminating toxicity with hard drug design. Curr Pharm Des. 2006;12:4649–4664. [PubMed]
83. Seneca N, Zoghbi SS, Liow JS, Kreisl W, Herscovitch P, Jenko K, et al. Human brain imaging and radiation dosimetry of 11C–N-desmethyl-loperamide, a PET radiotracer to measure the function of P-glycoprotein. J Nucl Med. 2009;50:807–813. [PMC free article] [PubMed]
84. Choo EF, Kurnik D, Muszkat M, Ohkubo T, Shay SD, Higginbotham JN, et al. Differential in vivo sensitivity to inhibition of P-glycoprotein located in lymphocytes, testes, and the blood-brain barrier. J Pharmacol Exp Ther. 2006;317:1012–1018. [PubMed]
85. Sadeque AJ, Wandel C, He H, Shah S, Wood AJ. Increased drug delivery to the brain by P-glycoprotein inhibition. Clin Pharmacol Ther. 2000;68:231–237. [PubMed]
86. Skarke C, Jarrar M, Schmidt H, Kauert G, Langer M, Geisslinger G, Lotsch J. Effects of ABCB1 (multidrug resistance transporter) gene mutations on disposition and central nervous effects of loperamide in healthy volunteers. Pharmacogenetics. 2003;13:651–660. [PubMed]
87. Mukwaya G, MacGregor T, Hoelscher D, Heming T, Legg D, Kavanaugh K, et al. Interaction of ritonavir-boosted tipranavir with loperamide does not result in loperamide-associated neurologic side effects in healthy volunteers. Antimicrob Agents Chemother. 2005;49:4903–4910. [PMC free article] [PubMed]
88. Wacher VJ, Wu CY, Benet LZ. Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy. Mol Carcinog. 1995;13:129–134. [PubMed]
89. Liu Y, Hunt CA. Mechanistic study of the cellular interplay of transport and metabolism using the synthetic modeling method. Pharm Res. 2006;23:493–505. [PubMed]
90. Marchetti S, Mazzanti R, Beijnen JH, Schellens JH. Concise review: clinical relevance of drug drug and herb drug interactions mediated by the ABC transporter ABCB1 (MDR1, P-glycoprotein) Oncologist. 2007;12:927–941. [PubMed]
91. Thomas H, Coley HM. Overcoming multidrug resistance in cancer: an update on the clinical strategy of inhibiting p-glycoprotein. Cancer Control. 2003;10:159–165. [PubMed]
92. Longley DB, Johnston PG. Molecular mechanisms of drug resistance. J Pathol. 2005;205:275–292. [PubMed]
93. Moscow JA, Cowan KH. Multidrug resistance. J Natl Cancer Inst. 1988;80:14–20. [PubMed]
94. Andersen MH, Sorensen RB, Schrama D, Svane IM, Becker JC, Thor Straten P. Cancer treatment: the combination of vaccination with other therapies. Cancer Immunol Immunother. 2008;57:1735–1743. [PMC free article] [PubMed]
95. Holland IB, Cole SPC, Kuchler K, Higgins CF, editors. ABC proteins: from bacteria to man. San Diego, CA, USA: Academic Press; 2003.
96. Loscher W, Potschka H. Role of multidrug transporters in pharmacoresistance to antiepileptic drugs. J Pharmacol Exp Ther. 2002;301:7–14. [PubMed]
97. Custodio JM, Wu CY, Benet LZ. Predicting drug disposition, absorption/ elimination/transporter interplay and the role of food on drug absorption. Adv Drug Deliv Rev. 2008;60:717–733. [PMC free article] [PubMed]
98. Seedhouse CH, Grundy M, White P, Li Y, Fisher J, Yakunina D, et al. Sequential influences of leukemia-specific and genetic factors on p-glycoprotein expression in blasts from 817 patients entered into the National Cancer Research Network acute myeloid leukemia 14 and 15 trials. Clin Cancer Res. 2007;13:7059–7066. [PubMed]
99. Chan HS, Haddad G, Thorner PS, DeBoer G, Lin YP, Ondrusek N, et al. P-glycoprotein expression as a predictor of the outcome of therapy for neuroblastoma. N Engl J Med. 1991;325:1608–1614. [PubMed]
100. Chan HS, Thorner PS, Haddad G, Ling V. Immunohistochemical detection of P-glycoprotein: prognostic correlation in soft tissue sarcoma of childhood. J Clin Oncol. 1990;8:689–704. [PubMed]
101. Chan HS, Thorner PS, Haddad G, DeBoer G, Gallie BL, Ling V. Multidrug resistance in cancers of childhood: clinical relevance and circumvention. Adv Pharmacol. 1993;24:157–197. [PubMed]
102. Bellamy WT. P-glycoproteins and multidrug resistance. Annu Rev Pharmacol Toxicol. 1996;36:161–183. [PubMed]
103. Salmon SE, Dalton WS, Grogan TM, Plezia P, Lehnert M, Roe DJ, Miller TP. Multidrug-resistant myeloma: laboratory and clinical effects of verapamil as a chemosensitizer. Blood. 1991;78:44–50. [PubMed]
104. Helgason HH, Kruijtzer CM, Huitema AD, Marcus SG, ten Bokkel Huinink WW, Schot ME, et al. Phase II and pharmacological study of oral paclitaxel (Paxoral) plus ciclosporin in anthracycline-pretreated metastatic breast cancer. Br J Cancer. 2006;95:794–800. [PMC free article] [PubMed]
105. Chu Z, Chen JS, Liau CT, Wang HM, Lin YC, Yang MH, et al. Oral bioavailability of a novel paclitaxel formulation (Genetaxyl) administered with cyclosporin A in cancer patients. Anticancer Drugs. 2008;19:275–281. [PMC free article] [PubMed]
106. Kruijtzer CM, Schellens JH, Mezger J, Scheulen ME, Keilholz U, Beijnen JH, et al. Phase II and pharmacologic study of weekly oral paclitaxel plus cyclosporine in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2002;20:4508–4516. [PubMed]
107. Morjani H, Madoulet C. Immunosuppressors as multidrug resistance reversal agents. Methods Mol Biol. 2010;596:433–446. [PubMed]
108. Twentyman PR. Cyclosporins as drug resistance modifiers. Biochem Pharmacol. 1992;43:109–117. [PubMed]
109. Meerum Terwogt JM, Malingre MM, Beijnen JH, ten Bokkel Huinink WW, Rosing H, Koopman FJ, et al. Coadministration of oral cyclosporin A enables oral therapy with paclitaxel. Clin Cancer Res. 1999;5:3379–3384. [PubMed]
110. Fischer V, Rodriguez-Gascon A, Heitz F, Tynes R, Hauck C, Cohen D, Vickers AE. The multidrug resistance modulator valspodar (PSC 833) is metabolized by human cytochrome P450 3A. Implications for drug-drug interactions and pharmacological activity of the main metabolite. Drug Metab Dispos. 1998;26:802–811. [PubMed]
111. Lagas JS, Vlaming ML, van Tellingen O, Wagenaar E, Jansen RS, Rosing H, et al. Multidrug resistance protein 2 is an important determinant of paclitaxel pharmacokinetics. Clin Cancer Res. 2006;12:6125–6132. [PubMed]
112. Lee CA, Neul D, Clouser-Roche A, Dalvie D, Wester MR, Jiang Y, et al. Identification of Novel Substrates for Human Cytochrome P450 2J2. Drug Metab Dispos. 2010;38:347–356. [PubMed]
113. Brooks TA, Minderman H, O’Loughlin KL, Pera P, Ojima I, Baer MR, Bernacki RJ. Taxane-based reversal agents modulate drug resistance mediated by P-glycoprotein, multidrug resistance protein, and breast cancer resistance protein. Mol Cancer Ther. 2003;2:1195–1205. [PubMed]
114. Tan B, Piwnica-Worms D, Ratner L. Multidrug resistance transporters and modulation. Curr Opin Oncol. 2000;12:450–458. [PubMed]
115. Planting AS, Sonneveld P, van der Gaast A, Sparreboom A, van der Burg ME, Luyten GP, et al. A phase I and pharmacologic study of the MDR converter GF120918 in combination with doxorubicin in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2005;55:91–99. [PubMed]
116. Kolitz JE, George SL, Dodge RK, Hurd DD, Powell BL, Allen SL, et al. Dose escalation studies of cytarabine, daunorubicin, and etoposide with and without multidrug resistance modulation with PSC-833 in untreated adults with acute myeloid leukemia younger than 60 years: final induction results of Cancer and Leukemia Group B Study 9621. J Clin Oncol. 2004;22:4290–4301. [PubMed]
117. Robey RW, Shukla S, Finley EM, Oldham RK, Barnett D, Ambudkar SV, et al. Inhibition of P-glycoprotein (ABCB1)- and multidrug resistance-associated protein 1 (ABCC1)-mediated transport by the orally administered inhibitor, CBT-1((R)) Biochem Pharmacol. 2008;75:1302–1312. [PMC free article] [PubMed]
118. Chen CC, Meadows B, Regis J, Kalafsky G, Fojo T, Carrasquillo JA, Bates SE. Detection of in vivo P-glycoprotein inhibition by PSC 833 using Tc-99m sestamibi. Clin Cancer Res. 1997;3:545–552. [PubMed]
119. Sekine I, Shimizu C, Nishio K, Saijo N, Tamura T. A literature review of molecular markers predictive of clinical response to cytotoxic chemotherapy in patients with breast cancer. Int J Clin Oncol. 2009;14:112–119. [PubMed]
120. Bates SE, Bakke S, Kang M, Robey RW, Zhai S, Thambi P, et al. A phase I/II study of infusional vinblastine with the P-glycoprotein antagonist valspodar (PSC 833) in renal cell carcinoma. Clin Cancer Res. 2004;10:4724–4733. [PubMed]
121. Bosch TM. Pharmacogenomics of drug-metabolizing enzymes and drug transporters in chemotherapy. Methods Mol Biol. 2008;448:63–76. [PubMed]
122. Tate SK, Sisodiya SM. Multidrug resistance in epilepsy: a pharmacogenomic update. Expert Opin Pharmacother. 2007;8:1441–1449. [PubMed]
123. Woodahl EL, Ho RJ. The role of MDR1 genetic polymorphisms in interindividual variability in P-glycoprotein expression and function. Curr Drug Metab. 2004;5:11–19. [PubMed]
124. Schuetz EG, Furuya KN, Schuetz JD. Interindividual variation in expression of P-glycoprotein in normal human liver and secondary hepatic neoplasms. J Pharmacol Exp Ther. 1995;275:1011–1018. [PubMed]
125. Wang D, Johnson AD, Papp AC, Kroetz DL, Sadee W. Multidrug resistance polypeptide 1 (MDR1, ABCB1) variant 3435C>T affects mRNA stability. Pharmacogenet Genomics. 2005;15:693–704. [PubMed]
126. Schaich M, Kestel L, Pfirrmann M, Robel K, Illmer T, Kramer M, et al. A MDR1 (ABCB1) gene single nucleotide polymorphism predicts outcome of temozolomide treatment in glioblastoma patients. Ann Oncol. 2009;20:175–181. [PubMed]
127. Zhang YT, Yang LP, Shao H, Li KX, Sun CH, Shi LW. ABCB1 polymorphisms may have a minor effect on ciclosporin blood concentrations in myasthenia gravis patients. Br J Clin Pharmacol. 2008;66:240–246. [PMC free article] [PubMed]
128. Mathijssen RH, Marsh S, Karlsson MO, Xie R, Baker SD, Verweij J, et al. Irinotecan pathway genotype analysis to predict pharmacokinetics. Clin Cancer Res. 2003;9:3246–3253. [PubMed]
129. Estrela Rde C, Ribeiro FS, Barroso PF, Tuyama M, Gregorio SP, Dias-Neto E, et al. ABCB1 polymorphisms and the concentrations of lopinavir and ritonavir in blood, semen and saliva of HIV-infected men under antiretroviral therapy. Pharmacogenomics. 2009;10:311–318. [PubMed]
130. Cascorbi I, Gerloff T, Johne A, Meisel C, Hoffmeyer S, Schwab M, et al. Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects. Clin Pharmacol Ther. 2001;69:169–174. [PubMed]
131. Yamauchi A, Ieiri I, Kataoka Y, Tanabe M, Nishizaki T, Oishi R, et al. Neurotoxicity induced by tacrolimus after liver transplantation: relation to genetic polymorphisms of the ABCB1 (MDR1) gene. Transplantation. 2002;74:571–572. [PubMed]
132. Sakaeda T, Nakamura T, Okumura K. Pharmacogenetics of MDR1 and its impact on the pharmacokinetics and pharmacodynamics of drugs. Pharmacogenomics. 2003;4:397–410. [PubMed]
133. Kim RB, Leake BF, Choo EF, Dresser GK, Kubba SV, Schwarz UI, et al. Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther. 2001;70:189–199. [PubMed]
134. Eichelbaum M, Fromm MF, Schwab M. Clinical aspects of the MDR1 (ABCB1) gene polymorphism. Ther Drug Monit. 2004;26:180–185. [PubMed]
135. Owen A, Goldring C, Morgan P, Chadwick D, Park BK, Pirmohamed M. Relationship between the C3435T and G2677T(A) polymorphisms in the ABCB1 gene and P-glycoprotein expression in human liver. Br J Clin Pharmacol. 2005;59:365–370. [PMC free article] [PubMed]
136. van den Heuvel-Eibrink MM, Wiemer EA, de Boevere MJ, van der Holt B, Vossebeld PJ, Pieters R, Sonneveld P. MDR1 gene-related clonal selection and P-glycoprotein function and expression in relapsed or refractory acute myeloid leukemia. Blood. 2001;97:3605–3611. [PubMed]
137. Oselin K, Gerloff T, Mrozikiewicz PM, Pahkla R, Roots I. MDR1 polymorphisms G2677T in exon 21 and C3435T in exon 26 fail to affect rhodamine 123 efflux in peripheral blood lymphocytes. Fundam Clin Pharmacol. 2003;17:463–469. [PubMed]
138. Morita N, Yasumori T, Nakayama K. Human MDR1 polymorphism: G2677T/ A and C3435T have no effect on MDR1 transport activities. Biochem Pharmacol. 2003;65:1843–1852. [PubMed]
139. Kroetz DL, Pauli-Magnus C, Hodges LM, Huang CC, Kawamoto M, Johns SJ, et al. Sequence diversity and haplotype structure in the human ABCB1 (MDR1, multidrug resistance transporter) gene. Pharmacogenetics. 2003;13:481–494. [PubMed]
140. Mai I, Perloff ES, Bauer S, Goldammer M, Johne A, Filler G, et al. MDR1 haplotypes derived from exons 21 and 26 do not affect the steady-state pharmacokinetics of tacrolimus in renal transplant patients. Br J Clin Pharmacol. 2004;58:548–553. [PMC free article] [PubMed]
141. Haas DW, Wu H, Li H, Bosch RJ, Lederman MM, Kuritzkes D, et al. MDR1 gene polymorphisms and phase 1 viral decay during HIV-1 infection: an adult AIDS Clinical Trials Group study. J Acquir Immune Defic Syndr. 2003;34:295–298. [PubMed]
142. Brant SR, Panhuysen CI, Nicolae D, Reddy DM, Bonen DK, Karaliukas R, et al. MDR1 Ala893 polymorphism is associated with inflammatory bowel disease. Am J Hum Genet. 2003;73:1282–1292. [PubMed]
143. Daniel F, Loriot MA, Seksik P, Cosnes J, Gornet JM, Lemann M, et al. Multidrug resistance gene-1 polymorphisms and resistance to cyclosporine A in patients with steroid resistant ulcerative colitis. Inflamm Bowel Dis. 2007;13:19–23. [PubMed]
144. Fischer S, Lakatos PL, Lakatos L, Kovacs A, Molnar T, Altorjay I, et al. ATP-binding cassette transporter ABCG2 (BCRP) and ABCB1 (MDR1) variants are not associated with disease susceptibility, disease phenotype response to medical therapy or need for surgery in Hungarian patients with inflammatory bowel diseases. Scand J Gastroenterol. 2007;42:726–733. [PubMed]
145. Ostergaard M, Ernst A, Labouriau R, Dagiliene E, Krarup HB, Christensen M, et al. Cyclooxygenase-2, multidrug resistance 1, and breast cancer resistance protein gene polymorphisms and inflammatory bowel disease in the Danish population. Scand J Gastroenterol. 2009;44:65–73. [PubMed]
146. Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmoller J, Johne A, et al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci U S A. 2000;97:3473–3478. [PubMed]
147. Sauer G, Kafka A, Grundmann R, Kreienberg R, Zeillinger R, Deissler H. Basal expression of the multidrug resistance gene 1 (MDR-1) is associated with the TT genotype at the polymorphic site C3435T in mammary and ovarian carcinoma cell lines. Cancer Lett. 2002;185:79–85. [PubMed]
148. Hitzl M, Drescher S, van der Kuip H, Schaffeler E, Fischer J, Schwab M, et al. The C3435T mutation in the human MDR1 gene is associated with altered efflux of the P-glycoprotein substrate rhodamine 123 from CD56+ natural killer cells. Pharmacogenetics. 2001;11:293–298. [PubMed]
149. Takane H, Kobayashi D, Hirota T, Kigawa J, Terakawa N, Otsubo K, Ieiri I. Haplotype-oriented genetic analysis and functional assessment of promoter variants in the MDR1 (ABCB1) gene. J Pharmacol Exp Ther. 2004;311:1179–1187. [PubMed]
150. Zhu D, Taguchi-Nakamura H, Goto M, Odawara T, Nakamura T, Yamada H, et al. Influence of single-nucleotide polymorphisms in the multidrug resistance-1 gene on the cellular export of nelfinavir and its clinical implication for highly active antiretroviral therapy. Antivir Ther. 2004;9:929–935. [PubMed]
151. Haas DW, Smeaton LM, Shafer RW, Robbins GK, Morse GD, Labbe L, et al. Pharmacogenetics of long-term responses to antiretroviral regimens containing Efavirenz and/or Nelfinavir: an Adult Aids Clinical Trials Group Study. J Infect Dis. 2005;192:1931–1942. [PubMed]
152. Drescher S, Schaeffeler E, Hitzl M, Hofmann U, Schwab M, Brinkmann U, et al. MDR1 gene polymorphisms and disposition of the P-glycoprotein substrate fexofenadine. Br J Clin Pharmacol. 2002;53:526–534. [PMC free article] [PubMed]
153. Rodriguez Novoa S, Barreiro P, Rendon A, Barrios A, Corral A, Jimenez-Nacher I, et al. Plasma levels of atazanavir and the risk of hyperbilirubinemia are predicted by the 3435C–T polymorphism at the multidrug resistance gene 1. Clin Infect Dis. 2006;42:291–295. [PubMed]
154. Asano T, Takahashi KA, Fujioka M, Inoue S, Okamoto M, Sugioka N, et al. ABCB1 C3435T and G2677T/A polymorphism decreased the risk for steroid-induced osteonecrosis of the femoral head after kidney transplantation. Pharmacogenetics. 2003;13:675–682. [PubMed]
155. Winzer R, Langmann P, Zilly M, Tollmann F, Schubert J, Klinker H, Weissbrich B. No influence of the P-glycoprotein genotype (MDR1 C3435T) on plasma levels of lopinavir and efavirenz during antiretroviral treatment. Eur J Med Res. 2003;8:531–534. [PubMed]
156. Putnam WS, Woo JM, Huang Y, Benet LZ. Effect of the MDR1 C3435T variant and P-glycoprotein induction on dicloxacillin pharmacokinetics. J Clin Pharmacol. 2005;45:411–421. [PubMed]
157. Pauli-Magnus C, Feiner J, Brett C, Lin E, Kroetz DL. No effect of MDR1 C3435T variant on loperamide disposition and central nervous system effects. Clin Pharmacol Ther. 2003;74:487–498. [PubMed]
158. Gerloff T, Schaefer M, Johne A, Oselin K, Meisel C, Cascorbi I, Roots I. MDR1 genotypes do not influence the absorption of a single oral dose of 1 mg digoxin in healthy white males. Br J Clin Pharmacol. 2002;54:610–616. [PMC free article] [PubMed]
159. Siddiqui A, Kerb R, Weale ME, Brinkmann U, Smith A, Goldstein DB, et al. Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCB1. N Engl J Med. 2003;348:1442–1448. [PubMed]
160. Hung CC, Jen Tai J, Kao PJ, Lin MS, Liou HH. Association of polymorphisms in NR1I2 and ABCB1 genes with epilepsy treatment responses. Pharmacogenomics. 2007;8:1151–1158. [PubMed]
161. Kwan P, Baum L, Wong V, Ng PW, Lui CH, Sin NC, et al. Association between ABCB1 C3435T polymorphism and drug-resistant epilepsy in Han Chinese. Epilepsy Behav. 2007;11:112–117. [PubMed]
162. Tan NC, Heron SE, Scheffer IE, Pelekanos JT, McMahon JM, Vears DF, et al. Failure to confirm association of a polymorphism i n ABCB1 with multidrug-resistant epilepsy. Neurology. 2004;63:1090–1092. [PubMed]
163. Vahab SA, Sen S, Ravindran N, Mony S, Mathew A, Vijayan N, et al. Analysis of genotype and haplotype effects of ABCB1 (MDR1) polymorphisms in the risk of medically refractory epilepsy in an Indian population. Drug Metab Pharmacokinet. 2009;24:255–260. [PubMed]
164. Tang K, Ngoi SM, Gwee PC, Chua JM, Lee EJ, Chong SS, Lee CG. Distinct haplotype profiles and strong linkage disequilibrium at the MDR1 multidrug transporter gene locus in three ethnic Asian populations. Pharmacogenetics. 2002;12:437–450. [PubMed]
165. The International HapMap Consortium: a haplotype map of the human genome. Nature. 2005;437:1299–1320. [PMC free article] [PubMed]
166. Jakobsson M, Scholz SW, Scheet P, Gibbs JR, VanLiere JM, Fung H-C, et al. Genotype, haplotype and copy-number variation in worldwide human populations. Nature. 2008;451:998–1003. [PubMed]
167. Allabi AC, Horsmans Y, Issaoui B, Gala JL. Single nucleotide polymorphisms of ABCB1 (MDR1) gene and distinct haplotype profile in a West Black African population. Eur J Clin Pharmacol. 2005;61:97–102. [PubMed]
168. Kimchi-Sarfaty C, Marple AH, Shinar S, Kimchi AM, Scavo D, Roma MI, et al. Ethnicity-related polymorphisms and haplotypes in the human ABCB1 gene. Pharmacogenomics. 2007;8:29–39. [PMC free article] [PubMed]
169. Robarge JD, Li L, Desta Z, Nguyen A, Flockhart DA. The star-allele nomenclature: retooling for translational genomics. Clin Pharmacol Ther. 2007;82:244–248. [PubMed]
170. Nebert DW. Suggestions for the nomenclature of human alleles: relevance to ecogenetics, pharmacogenetics and molecular epidemiology. Pharmacogenetics. 2000;10:279–290. [PubMed]
171. Jiang ZP, Xu P, Liu RR, Li HD, Wang GP, Zhao XL, Chen FP. Correlation between MDR1 methylation status in the promoter region and MDR1 genetic polymorphism in 194 healthy Chinese Han subjects. Pharmacogenomics. 2008;9:1801–1808. [PubMed]
172. Zimprich F, Sunder-Plassmann R, Stogmann E, Gleiss A, Dal-Bianco A, Zimprich A, et al. Association of an ABCB1 gene haplotype with pharmacoresistance in temporal lobe epilepsy. Neurology. 2004;63:1087–1089. [PubMed]
173. Hung CC, Tai JJ, Lin CJ, Lee MJ, Liou HH. Complex haplotypic effects of the ABCB1 gene on epilepsy treatment response. Pharmacogenomics. 2005;6:411–417. [PubMed]
174. Aarnoudse AJ, Dieleman JP, Visser LE, Arp PP, van der Heiden IP, van Schaik RH, et al. Common ATP-binding cassette B1 variants are associated with increased digoxin serum concentration. Pharmacogenet Genomics. 2008;18:299–305. [PubMed]
175. Xu P, Jiang ZP, Zhang BK, Tu JY, Li HD. Impact of MDR1 haplotypes derived from C1236T, G2677T/A and C3435T on the pharmacokinetics of single-dose oral digoxin in healthy Chinese volunteers. Pharmacology. 2008;82:221–227. [PubMed]
176. Sai K, Itoda M, Saito Y, Kurose K, Katori N, Kaniwa N, et al. Genetic variations and haplotype structures of the ABCB1 gene in a Japanese population: an expanded haplotype block covering the distal promoter region, and associated ethnic differences. Ann Hum Genet. 2006;70:605–622. [PubMed]