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1.  Expression of SLCO transport genes in castration resistant prostate cancer and impact of genetic variation in SCLO1B3 and SLCO2B1 on prostate cancer outcomes 
Background
Metastases from men with castration resistant prostate cancer (CRPC) harbor increased tumoral androgens vs. untreated prostate cancers (PCa). This may reflect steroid uptake by OATP/SLCO transporters. We evaluated SLCO gene expression in CRPC metastases and determined whether PCa outcomes are associated with single nucleotide polymorphisms (SNPs) in SLCO2B1 and SLCO1B3, transporters previously demonstrated to mediate androgen uptake.
Methods
Transcripts encoding 11 SLCO genes were analyzed in untreated PCa, and in metastatic CRPC tumors obtained by rapid autopsy. SNPs in SLCO2B1 and SLCO1B3 were genotyped in a population-based cohort of 1,309 Caucasian PCa patients. Median survival follow-up was 7.0 years (0.77–16.4). The risk of PCa recurrence/progression and PCa-specific mortality (PCSM) was estimated with Cox proportional hazards analysis.
Results
Six SLCO genes were highly expressed in CRPC metastases vs. untreated PCa, including SLCO1B3 (3.6 fold, p=0.0517) and SLCO2B1 (5.5 fold, p=0.0034). Carriers of the variant alleles SLCO2B1 SNP rs12422149 (HR 1.99, 95% CI 1.11 – 3.55) or SLCO1B3 SNP rs4149117 (HR 1.76, 95% CI 1.00 – 3.08) had an increased risk of PCSM.
Conclusions
CRPC metastases demonstrate increased expression of SLCO genes vs. primary PCa. Genetic variants of SLCO1B3 and SLCO2B1 are associated with PCSM. Expression and genetic variation of SLCO genes which alter androgen uptake may be important in PCa outcomes.
Impact
OATP/SLCO genes may be potential biomarkers for assessing risk of prostate cancer-specific mortality. Expression and genetic variation in these genes may allow stratification of patients to more aggressive hormonal therapy or earlier incorporation of non-hormonal based treatment strategies.
doi:10.1158/1055-9965.EPI-10-1023
PMCID: PMC3073610  PMID: 21266523
prostate cancer; castration resistant; SLCO; steroid transport; genetic variation
2.  Effect of drug transporter genotypes on pravastatin disposition in European- and African-American participants 
Pharmacogenetics and genomics  2007;17(8):647-656.
Objective
Our aims were to evaluate the effects of polymorphisms in the hepatic drug uptake transporter organic anion transporting polypeptide 1B1 (OATP1B1, SLCO1B1) and efflux transporters multidrug resistance-associated protein 2 (MRP2, ABCC2), bile salt export pump (BSEP, ABCB11), and breast cancer-related protein (BCRP, ABCG2) on single-dose pravastatin pharmacokinetics in healthy European- and African-American participants.
Methods
The pharmacokinetics of a single oral 40mg dose of pravastatin was determined in 107 participants (69 European-Americans and 38 African-Americans). Participants were genotyped for known OATP1B1, MRP2, BSEP, and BCRP polymorphisms. Baseline serum total and unconjugated plasma bilirubin concentrations were also determined.
Results
OATP1B1 genotypes were ethnicity-dependent with a 521C allele frequency of ~15% in European-Americans and ~1% in African-Americans. SLCO1B1 521TC genotype was associated with significantly higher pravastatin area under the curve [AUC(0–5)] (P =0.01) and Cmax values (P< 0.05). When analyzed by diplotype, SLCO1B1*1a/*15 (N =8) participants exhibited 45 and 80% higher AUC values than SLCO1B1*1a/*1a (N=29) (P=0.013) and SLCO1B1*1b/*1b (N=34) (P=0.001) carriers, respectively. SLCO1B1*15/*15 (N=2) participants exhibited 92 and 149% higher AUC values than SLCO1B1*1a/*1a (P=0.017) and SLCO1B1*1b/*1b (P= 0.011) carriers, respectively. European-Americans had significantly higher plasma pravastatin AUC(0–5) (P =0.01) and Cmax values (P=0.009) than African-Americans. Neither ABCC2, ABCB11, nor ABCG2 genotypes were associated with differences in pravastatin pharmacokinetics. We did not observe an effect of SLCO1B1 genotype on baseline total or unconjugated bilirubin levels.
Conclusion
SLCO1B1 genotype, in particular the 521C allele, had a significant effect on the pharmacokinetics of pravastatin. Even when adjusted for the presence of the SLCO1B1 521C or 388G variant allele, European-Americans demonstrated significantly higher pravastatin AUC and Cmax values than African-Americans.
doi:10.1097/FPC.0b013e3280ef698f
PMCID: PMC4063287  PMID: 17622941
ABCB11; ABCC2; ABCG2; BCRP; bilirubin; BSEP; MRP2; OATP1B1; pharmacokinetics; pravastatin; SLCO1B1; transporter
3.  The cyclin-dependent kinase inhibitor flavopiridol potentiates doxorubicin efficacy in advanced sarcomas: preclinical investigations and results of a phase I dose escalation clinical trial 
Clinical Cancer Research  2012;18(9):2638-2647.
Background
Dysregulated cyclin-dependent kinases (CDKs) are important to the growth of some sarcomas. Flavopiridol is a pan-CDK inhibitor that has been shown to potentiate chemotherapy. As such, we explored the potentiation of doxorubicin by flavopiridol in sarcoma, in vitro and in vivo, and performed a phase I trial of flavopiridol with doxorubicin in patients with advanced sarcomas.
Design
Sarcoma cell lines and xenografts were treated with flavopiridol alone and in combination with doxorubicin. In the phase I study, doxorubicin and flavopiridol were administered on 2 flavopiridol schedules; a 1 hour bolus and split dosing as a 30 minute bolus followed by a 4 hour infusion.
Results
Pre-clinically, flavopiridol potentiated doxorubicin. In vivo, doxorubicin administered 1 hour prior to flavopiridol was more active than doxorubicin alone. Clinically, 31 patients were enrolled on protocol and flavopiridol was escalated to target dose in 2 schedules (90 mg/m2 bolus; 50 mg/m2 bolus + 40 mg/m2 infusion) both in combination with doxorubicin (60 mg/m2). Dose-limiting toxicities were neutropenia, leukopenia and febrile neutropenia but no maximum tolerated dose was defined. Flavopiridol pharmacokinetics showed increasing Cmax with increasing dose. RECIST responses included 2 partial responses however stable disease was seen in 16 patients. Of 12 evaluable patients with progressive well- and de-differentiated liposarcoma, 8 had stable disease greater than 12 weeks.
Conclusions
The sequential combination of doxorubicin followed flavopiridol is well tolerated on both schedules. Disease control was observed in well- and de-differentiated liposarcoma specifically, a disease where CDK4 is known to be amplified.
doi:10.1158/1078-0432.CCR-11-3203
PMCID: PMC3343204  PMID: 22374332
Flavopiridol; Sarcoma; Cyclin-dependent kinase; CDK; phase I
4.  Comprehensive Pharmacogenetic Analysis of Irinotecan Neutropenia and Pharmacokinetics 
Journal of Clinical Oncology  2009;27(16):2604-2614.
Purpose
We aim to identify genetic variation, in addition to the UGT1A1*28 polymorphism, that can explain the variability in irinotecan (CPT-11) pharmacokinetics and neutropenia in cancer patients.
Patients and Methods
Pharmacokinetic, genetic, and clinical data were obtained from 85 advanced cancer patients treated with single-agent CPT-11 every 3 weeks at doses of 300 mg/m2 (n = 20) and 350 mg/m2 (n = 65). Forty-two common variants were genotyped in 12 candidate genes of the CPT-11 pathway using several methodologies. Univariate and multivariate models of absolute neutrophil count (ANC) nadir and pharmacokinetic parameters were evaluated.
Results
Almost 50% of the variation in ANC nadir is explained by UGT1A1*93, ABCC1 IVS11 –48C>T, SLCO1B1*1b, ANC baseline levels, sex, and race (P < .0001). More than 40% of the variation in CPT-11 area under the curve (AUC) is explained by ABCC2 –24C>T, SLCO1B1*5, HNF1A 79A>C, age, and CPT-11 dose (P < .0001). Almost 30% of the variability in SN-38 (the active metabolite of CPT-11) AUC is explained by ABCC1 1684T>C, ABCB1 IVS9 –44A>G, and UGT1A1*93 (P = .004). Other models explained 17%, 23%, and 27% of the variation in APC (a metabolite of CPT-11), SN-38 glucuronide (SN-38G), and SN-38G/SN-38 AUCs, respectively. When tested in univariate models, pretreatment total bilirubin was able to modify the existing associations between genotypes and phenotypes.
Conclusion
On the basis of this exploratory analysis, common polymorphisms in genes encoding for ABC and SLC transporters may have a significant impact on the pharmacokinetics and pharmacodynamics of CPT-11. Confirmatory studies are required.
doi:10.1200/JCO.2008.20.6300
PMCID: PMC2690389  PMID: 19349540
5.  Genetics is a major determinant of expression of the human hepatic uptake transporter OATP1B1, but not of OATP1B3 and OATP2B1 
Genome Medicine  2013;5(1):1.
Background
Organic anion transporting polypeptide (OATP) 1B1, OATP1B3, and OATP2B1 (encoded by SLCO1B1, SLCO1B3, SLCO2B1) mediate the hepatic uptake of endogenous compounds like bile acids and of drugs, for example, the lipid-lowering atorvastatin, thereby influencing hepatobiliary elimination. Here we systematically elucidated the contribution of SLCO variants on expression of the three hepatic OATPs under consideration of additional important covariates.
Methods
Expression was quantified by RT-PCR and immunoblotting in 143 Caucasian liver samples. A total of 109 rare and common variants in the SLCO1B3-SLCO1B1 genomic region and the SLCO2B1 gene were genotyped by MALDI-TOF mass spectrometry and genome-wide SNP microarray technology. SLCO1B1 haplotypes affecting hepatic OATP1B1 expression were associated with pharmacokinetic data of the OATP1B1 substrate atorvastatin (n = 82).
Results
Expression of OATP1B1, OATP1B3, and OATP2B1 at the mRNA and protein levels showed marked interindividual variability. All three OATPs were expressed in a coordinated fashion. By a multivariate regression analysis adjusted for non-genetic and transcription covariates, increased OATP1B1 expression was associated with the coding SLCO1B1 variant c.388A > G (rs2306283) even after correction for multiple testing (P = 0.00034). This held true for haplotypes harboring c.388A > G but not the functional variant c.521T > C (rs4149056) associated with statin-related myopathy. c.388A > G also significantly affected atorvastatin pharmacokinetics. SLCO variants and non-genetic and regulatory covariates together accounted for 59% of variability of OATP1B1 expression.
Conclusions
Our results show that expression of OATP1B1, but not of OATP1B3 and OATP2B1, is significantly affected by genetic variants. The SLCO1B1 variant c.388A > G is the major determinant with additional consequences on atorvastatin plasma levels.
doi:10.1186/gm405
PMCID: PMC3706890  PMID: 23311897
6.  A Phase I Study of Flavopiridol Administered with Oxaliplatin and Fluorouracil/Leucovorin (FOLFOX) in Advanced Solid Tumors: Encouraging Activity in Refractory Germ Cell Tumors 
Purpose
Flavopiridol, a cyclin-dependent kinase inhibitor, has promising clinical activity when combined with chemotherapy. Preclinical data indicate that flavopiridol enhances oxaliplatin (OX)- and fluorouracil (5FU)-induced apoptosis in a sequence-dependent manner.
Experimental Design
We conducted a phase I trial of flavopiridol + FOLFOX (folinic acid, 5FU, and OX) for advanced solid tumors. Flavopiridol was administered every two weeks with OX before 5FU, based on sequence-dependent growth inhibition. Flavopiridol pharmacokinetics and p53 status were evaluated.
Results
Forty-eight patients were treated on study. With dose escalation of OX (85 mg/m2) and 5FU (2400 mg/m2), dose-limiting toxicities (DLT) included hyponatremia, thrombocytopenia, and neutropenia. 5FU was subsequently reduced to allow for dose escalation of flavopiridol. DLTs with escalation of flavopiridol were nausea, vomiting, and neutropenia. The maximum tolerated dose (MTD) was flavopiridol 70 mg/m2, oxaliplatin 85 mg/m2, and 5FU 1800 mg/m2 continuous infusion over 48 hours. Clinical activity was noted in platinum-refractory germ cell tumors (GCTs): 3 out of 9 (33%) evaluable patients demonstrated a partial response on imaging, and 7 out of 10 (70%) had a decline in serum tumor markers. Responses were also observed in pancreatic, gastric, and sweat gland tumors. Flavopiridol pharmacokinetics had significant interpatient variability. At the MTD, tumor samples were p53 mutant (>30% positive cells) for responders and p53 wild-type for non-responders.
Conclusions
Flavopiridol with FOLFOX is a safe and tolerable regimen. Promising clinical activity was seen across tumor types. Encouraging results in the platinum-refractory GCT population has prompted a phase II trial which is currently open for accrual.
doi:10.1158/1078-0432.CCR-09-1502
PMCID: PMC2787644  PMID: 19934304
flavopiridol; FOLFOX; germ cell tumor; solid tumor; refractory
7.  A phase I clinical trial of FOLFIRI in combination with the pan-cyclin-dependent kinase (CDK) inhibitor flavopiridol 
Cancer chemotherapy and pharmacology  2010;66(6):1113-1121.
Background
The cyclin-dependent kinase inhibitor flavopiridol increases irinotecan- and fluorouracil-induced apoptosis. We conducted a phase I trial of FOLFIRI + flavopiridol in patients with advanced solid tumors.
Design
FOLFIRI + flavopiridol were administered every 2 weeks. Based on sequence-dependent inhibition, flavopiridol was given 3 h after irinotecan but before 5-FU. Two maximum tolerated doses were determined, one with flavopiridol administered over 1 h, and one with flavopiridol split as a 30-min bolus followed by a 4-h infusion.
Results
A total of 74 patients were enrolled and 63 were evaluable. The MTD with FOLFIRI was flavopiridol 80 mg/m2 over 1 h or 35 mg/m2 bolus + 35 mg/m2 over 4 h. Dose-limiting toxicities were diarrhea, fatigue, neutropenia, and neuropathy. Clinical activity included 2 partial responses in small bowel cancer and bladder cancer and 1 complete response in mucosal melanoma. Stable disease was seen in 22 patients. Pharmacokinetic studies showed increasing Cmax with increasing flavopiridol dose. Clinical benefit was correlated with the presence of wild-type p53. Of 25 patients with colorectal cancer, 11 had as best response SD for >3 m (median 6 m, range 4.2–15.4 m), despite failing ≥1 irinotecan-containing regimen.
Conclusions
Treatment with flavopiridol and FOLFIRI is a safe and effective regimen. Concentrations of flavopiridol that enhance the effects of FOLFIRI can be achieved. Clinical activity is encouraging and includes prolonged stable disease in patients with irinotecan-refractory colorectal cancer.
doi:10.1007/s00280-010-1269-1
PMCID: PMC2957673  PMID: 20953860
CDKs and CDK inhibitors; Phase I trials; Gastrointestinal cancers: colorectal; Combination chemotherapy; Pharmacokinetics and pharmacodynamics; Novel antitumor agents
8.  No significant effect of SLCO1B1 polymorphism on the pharmacokinetics of rosiglitazone and pioglitazone 
AIMS
To examine possible effects of polymorphism in the SLCO1B1 gene, encoding the hepatic uptake transporter organic anion transporting polypeptide (OATP) 1B1, on the pharmacokinetics of rosiglitazone and pioglitazone in a prospective genotype panel study.
METHODS
Sixteen healthy volunteers with the homozygous SLCO1B1 c.521TT genotype (controls), 12 with the heterozygous c.521TC genotype and four with the homozygous c.521CC genotype ingested a single 4-mg dose of rosiglitazone and a single 15-mg dose of pioglitazone in a cross-over study with a wash-out period of at least 1 week.
RESULTS
SLCO1B1 polymorphism had no statistically significant effect on any of the pharmacokinetic variables of rosiglitazone, pioglitazone or their metabolites. The mean ± SD area under the plasma rosiglitazone concentration–time curve from time 0 to infinity (AUC0–∞) was 2024 ± 561 ng ml−1 h in the c.521TT subjects, 1763 ± 288 ng ml−1 h in the c.521TC subjects (geometric mean ratio c.521TC/c.521TT 0.89; 95% confidence interval 0.72, 1.11) and 1729 ± 346 ng ml−1 h in the c.521CC subjects (c.521CC/c.521TT 0.87; 0.63, 1.20). The AUC0–∞ of pioglitazone averaged 6244 ± 1909 ng ml−1 h in the c.521TT subjects, 5123 ± 1165 ng ml−1 h in the c.521TC subjects (c.521TC/c.521TT 0.83; 0.65, 1.06) and 4851 ± 1123 ng ml−1 h in the c.521CC subjects (c.521CC/c.521TT 0.79; 0.55, 1.14). There was a significant correlation between the AUC0–∞ of rosiglitazone and pioglitazone (r = 0.717, P < 0.001).
CONCLUSIONS
The SLCO1B1 c.521T→C SNP does not affect the pharmacokinetics of rosiglitazone or pioglitazone, indicating that OATP1B1 plays no significant role in the disposition of these drugs.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECTA common single nucleotide polymorphism (SNP) (c.521T→C) of the SLCO1B1 gene, encoding the hepatic uptake transporter organic anion transporting polypeptide (OATP) 1B1, has been associated with marked changes in the pharmacokinetics of the antidiabetic drug repaglinide.Rosiglitazone and pioglitazone are competitive inhibitors of OATP1B1 and might thus be its substrates.Gemfibrozil, an inhibitor of OATP1B1 in vitro, considerably increases the plasma concentrations of rosiglitazone and pioglitazone in vivo in humans.
WHAT THIS STUDY ADDSThe SLCO1B1 c.521T→C SNP was not associated with changes in rosiglitazone or pioglitazone pharmacokinetics in healthy volunteers.OATP1B1 is thus unlikely to play an important role in the disposition of rosiglitazone or pioglitazone.
doi:10.1111/j.1365-2125.2007.02986.x
PMCID: PMC2291278  PMID: 17635496
OATP1B1; pharmacogenetics; pharmacokinetics; pioglitazone; rosiglitazone; SLCO1B1
9.  SLCO1B1 521T→C functional genetic polymorphism and lipid-lowering efficacy of multiple-dose pravastatin in Chinese coronary heart disease patients 
What is already known about this subject Both oral clearance as well as delivery of pravastatin to its molecular targets in hepatoctyes are greatly influenced by the organic anion transporting polypeptide 1B1 (OATP1B1), encoded by SLCO1B1.The role of genetic factors that determine the marked interindividual variability in lipid-lowering efficacy of pravastatin in Chinese patients is not known.The present study was designed to evaluate the impact of a common functional genetic polymorphism in SLCO1B1 (521T→C: Val174Ala) on pravastatin efficacy in Chinese patients with coronary heart disease.
What this study adds
521T→C functional genetic polymorphism of SLCO1B1 is significantly associated with an attenuated total cholesterol-lowering efficacy of pravastatin in Chinese patients with coronary heart disease.
Aims
Pravastatin is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, which is widely used both in primary and secondary prevention of coronary heart disease (CHD). Pravastatin is not subject to metabolism by cytochrome P450s, but it is actively transported from blood into target tissues (e.g. hepatocytes in the liver) by the organic anion transporting polypeptide 1B1 (OATP1B1), encoded by SLCO1B1. The aim of the present study was to evaluate the impact of SLCO1B1 521T→C (Val174Ala) functional genetic polymorphism on the lipid-lowering efficacy of multiple-dose pravastatin in Chinese patients with CHD.
Methods
Forty-five hospitalized patients with CHD prospectively received pravastatin as a single-agent therapy (20 mg day−1 p.o.) for 30 days. Serum triglycerides, total cholesterol, low-density lipoprotein-cholesterol and high-density lipoprotein-cholesterol concentrations were determined before and after pravastatin treatment.
Results
Pravastatin treatment significantly decreased plasma lipids in all patients (P< 0.001). Importantly, we showed an attenuated pravastatin pharmacodynamic effect on total cholesterol in patients with 521TC heterozygote genotype (from 5.52 ± 0.51 mmol l−1 to 4.70 ± 0.35 mmol l−1, % change −14.5 ± 6.6%, N = 9) compared with 521TT homozygote genotype (from 5.47 ± 1.15 mmol l−1 to 4.21 ± 0.89 mmol l−1, % change −22.4 ± 10.3%, N = 36) (mean ± SD, P = 0.03, two-tailed test with α set at 5%). SLCO1B1 521T→C functional polymorphism did not significantly influence pravastatin pharmacodynamics on other plasma lipids (P > 0.05).
Conclusions
The 521T→C polymorphism of SLCO1B1 appears to modulate significantly the total cholesterol-lowering efficacy of pravastatin in Chinese patients with CHD. Further studies are warranted to determine the extent to which SLCO1B1 genetic variation may contribute to resistance to pravastatin in Asian patients treated with standard doses of pravastatin.
doi:10.1111/j.1365-2125.2007.02892.x
PMCID: PMC2000640  PMID: 17439540
coronary heart disease; functional polymorphism; interethnic variation; pharmacogenetic variation; pravastatin efficacy; SLCO1B1
10.  Germline Genetic Variation in an Organic Anion Transporter Polypeptide Associated With Methotrexate Pharmacokinetics and Clinical Effects 
Journal of Clinical Oncology  2009;27(35):5972-5978.
Purpose
Methotrexate plasma concentration is related to its clinical effects. Our aim was to identify the genetic basis of interindividual variability in methotrexate pharmacokinetics in children with newly diagnosed acute lymphoblastic leukemia (ALL).
Patients and Methods
We performed a genome-wide analysis of 500,568 germline single-nucleotide polymorphisms (SNPs) to identify how inheritance affects methotrexate plasma disposition among 434 children with ALL who received 3,014 courses of methotrexate at 2 to 5 g/m2. SNPs were validated in an independent cohort of 206 patients.
Results
Adjusting for age, race, sex, and methotrexate regimen, the most significant associations were with SNPs in the organic anion transporter polypeptide, SLCO1B1. Two SNPs in SLCO1B1, rs11045879 (P = 1.7 × 10−10) and rs4149081 (P = 1.7 × 10−9), were in linkage disequilibrium (LD) with each other (r2 = 1) and with a functional polymorphism in SLCO1B1, T521C (rs4149056; r2 > 0.84). rs11045879 and rs4149081 were validated in an independent cohort of 206 patients (P = .018 and P = .017), as were other SLCO1B1 SNPs residing in different LD blocks. SNPs in SLCO1B1 were also associated with GI toxicity (odds ratio, 15.3 to 16.4; P = .03 to .004).
Conclusion
A genome-wide interrogation identified inherited variations in a plausible, yet heretofore low-priority candidate gene, SLCO1B1, as important determinants of methotrexate's pharmacokinetics and clinical effects.
doi:10.1200/JCO.2008.20.4156
PMCID: PMC2793040  PMID: 19901119
11.  Effect of SLCO1B3 haplotype on testosterone transport and clinical outcome in Caucasian patients with androgen-independent prostatic cancer 
Purpose
The organic anion transporter OATP1B3, encoded by SLCO1B3, is involved in the transport of steroid hormones. However, its role in testosterone uptake and clinical outcome of prostatic cancer is unknown. This study examined: 1) the SLCO1B3 genotype in cancer cells as well as the uptake of testosterone by cells transfected with genetic variants of SLCO1B3; 2) the expression of OATP1B3 in normal prostate, benign prostatic hyperplasia and prostatic cancer, and 3) the role of SLCO1B3 haplotype on clinical outcome of Caucasian patients with androgen-independent prostatic cancer.
Experimental design
SLCO1B3 genotype was assessed in the NCI-60 panel of tumor cells by sequencing, while testosterone transport was analyzed in Cos-7 cells transfected with wild-type (WT), 334G and 699A SLCO1B3 variants. OATP1B3 expression in prostatic tissues was examined by fluorescence microscopy and the relationship between SLCO1B3 haplotypes and survival was examined in patients.
Results
Cells transfected with WT (334T/699G) SLCO1B3, or with a vector containing either the 334G or 699A variants, actively transported testosterone, while its uptake was impaired in cells transfected with a gene carrying both 334G and 699A SNPs. Prostatic cancer over-expresses OATP1B3 compared to normal or benign hyperplastic tissue; patients with SLCO1B3 334GG/699AA haplotype, showed longer median survival (8.5 vs. 6.4 years, p=0.020) and improved survival probability at 10 years (42 vs. 23%, p<0.023) than patients carrying TT/AA and TG/GA haplotypes.
Conclusions
The common SLCO1B3 GG/AA haplotype is associated with impaired testosterone transport and improved survival in patients with prostatic cancer.
doi:10.1158/1078-0432.CCR-07-4118
PMCID: PMC2701141  PMID: 18519758
12.  Effects of Tuberculosis, Race, and Human Gene SLCO1B1 Polymorphisms on Rifampin Concentrations▿ ‖  
Antimicrobial Agents and Chemotherapy  2010;54(10):4192-4200.
Rifampin has concentration-dependent activity against Mycobacterium tuberculosis. However, marked intersubject variation of rifampin concentrations occurs. In this study, we evaluated rifampin pharmacokinetics in relation to tuberculosis, geographic region, race, and single nucleotide polymorphisms of the human transporter genes SLCO1B1, SLCO1B3, and MDR1. Seventy-two adults with pulmonary tuberculosis from Africa, North America, and Spain were evaluated during multidrug intensive-phase therapy, and their results were compared to those from 16 healthy controls from North America. Rifampin pharmacokinetic values were similar between tuberculosis patients and controls (geometric mean [GM] area under the concentration-time curve from 0 to 24 h [AUC0-24] of 40.2 versus 40.9 μg·h/ml; P = 0.9). However, in multivariable analyses, the rifampin AUC0-24 was significantly affected by rifampin dosage (in mg/kg of body weight), polymorphisms in the SLCO1B1 gene, and the presence of tuberculosis by geographic region. The adjusted rifampin AUC0-24 was lowest in patients with tuberculosis from Africa compared to that in non-African patients or control subjects. The adjusted rifampin AUC0-24 was also 36% lower among participants with SLCO1B1 genotype c.463CA than that among participants with SLCO1B1 genotype c.463CC (adjusted GM, 29.8 versus 46.7 μg·h/ml; P = 0.001). Polymorphisms in the SLCO1B1 gene associated with lower rifampin exposure were more frequent among black subjects. In conclusion, marked intersubject variation of the rifampin AUC0-24 values was observed, but the mean values of the AUC0-24 did not significantly vary between patients with tuberculosis and healthy controls. Lower rifampin exposure was associated with the polymorphism of the SLCO1B1 c.463C>A gene. When adjusted for the patient mg/kg dosage and transporter gene polymorphisms, rifampin exposure was lower in patients with tuberculosis, which suggests that additional absorption or metabolic processes affect rifampin exposure with tuberculosis disease.
doi:10.1128/AAC.00353-10
PMCID: PMC2944564  PMID: 20660695
13.  CYP3A5, ABCB1 and SLCO1B1 Polymorphisms and Pharmacokinetics and Virologic Outcome of Lopinavir/Ritonavir in HIV-infected Children 
Therapeutic drug monitoring  2011;33(4):417-424.
Objective
CYP3A5, MDR1 (ABCB1) and OATP1 (SLCO1B1) polymorphisms have been associated with variability in the pharmacokinetics (PK) of protease inhibitors. The aim of this study was to investigate the influence of CYP3A5 A6986G, ABCB1 (C3435T and G2677T), and SLCO1B1 (T521C and A388AG) polymorphisms on the PK and virologic outcome of lopinavir/ritonavir (LPV/RTV) in HIV-infected children.
Design and Methods
Prospective cohort study in children (4-18 yrs old) on stable antiretroviral therapy with LPV/RTV. CYP3A5, ABCB1 and SLCO1B1 genotypes were determined using PCR amplification with allelic discrimination assays. The 12 hr plasma area under the concentration-time curves (AUC) and clearances (CL) of LPV and RTV were estimated using non-compartmental models. HIV RNA viral load was evaluated every 12 weeks for a total study period of 52 weeks. Analysis of covariance models with adjustment for age and adherence, and allometric adjustment of CL were used to assess associations between studied polymorphisms and AUC, CL and HIV RNA.
Results
50 children (median age 11.2 yrs) were enrolled. Allele frequencies of studied genotypes were in Hardy-Weinberg equilibrium. There was no statistically significant association between LPV or RTV AUC or CL, and CYP3A5, ABCB1 or SLCO1B1 A388G polymorphisms. There was a significant association between SLCO1B1 T521C genotype and increased LPV AUC (p=0.042) and a nearly significant association with decreased LPV CL (p=0.063). None of the studied polymorphisms including SLCO1B1 T521C were associated with virologic outcome during 52 weeks of study follow up.
Conclusions
There was no statistically significant influence of the CYP3A5, ABCB1 or SLCO1B1 A388AG polymorphisms on the PK and virologic outcome of LPV/RTV in HIV-infected children. SLCO1B1 T521C polymorphism was significantly associated with increase in LPV AUC, but was not associated with undetectable HIV RNA during the study period.
doi:10.1097/FTD.0b013e318225384f
PMCID: PMC3139013  PMID: 21743379
Lopinavir; Ritonavir; CYP3A5; ABCB1; SLCO1B1; HIV; children
14.  Organic anion transporting polypeptide 1a/1b–knockout mice provide insights into hepatic handling of bilirubin, bile acids, and drugs 
The Journal of Clinical Investigation  2010;120(8):2942-2952.
Organic anion transporting polypeptides (OATPs) are uptake transporters for a broad range of endogenous compounds and xenobiotics. To investigate the physiologic and pharmacologic roles of OATPs of the 1A and 1B subfamilies, we generated mice lacking all established and predicted mouse Oatp1a/1b transporters (referred to as Slco1a/1b–/– mice, as SLCO genes encode OATPs). Slco1a/1b–/– mice were viable and fertile but exhibited markedly increased plasma levels of bilirubin conjugated to glucuronide and increased plasma levels of unconjugated bile acids. The unexpected conjugated hyperbilirubinemia indicates that Oatp1a/1b transporters normally mediate extensive hepatic reuptake of glucuronidated bilirubin. We therefore hypothesized that substantial sinusoidal secretion and subsequent Oatp1a/1b-mediated reuptake of glucuronidated compounds can occur in hepatocytes under physiologic conditions. This alters our perspective on normal liver functioning. Slco1a/1b–/– mice also showed drastically decreased hepatic uptake and consequently increased systemic exposure following i.v. or oral administration of the OATP substrate drugs methotrexate and fexofenadine. Importantly, intestinal absorption of oral methotrexate or fexofenadine was not affected in Slco1a/1b–/– mice. Further analysis showed that rifampicin was an effective and specific Oatp1a/1b inhibitor in controlling methotrexate pharmacokinetics. These data indicate that Oatp1a/1b transporters play an essential role in hepatic reuptake of conjugated bilirubin and uptake of unconjugated bile acids and drugs. Slco1a/1b–/– mice will provide excellent tools to study further the role of Oatp1a/1b transporters in physiology and drug disposition.
doi:10.1172/JCI42168
PMCID: PMC2912192  PMID: 20644253
15.  The effect of SLCO1B1 polymorphism on repaglinide pharmacokinetics persists over a wide dose range 
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECTOrganic anion transporting polypeptide 1B1 is an influx transporter expressed on the basolateral membrane of hepatocytes.A common single nucleotide polymorphism, c.521T→C (p.Val174Ala), of the SLCO1B1 gene has been associated with increased plasma repaglinide concentrations in healthy volunteers.Previous studies at low repaglinide doses have suggested that the effect of SLCO1B1 c.521T→C polymorphism on the pharmacokinetics of repaglinide could be dose-dependent. WHAT THIS STUDY ADDSRepaglinide peak plasma concentration and area under the plasma concentration–time curve increased linearly along with repaglinide dose ranging from 0.25 to 2 mg in both the predominant c.521TT and rare c.521CC genotype group.The effect of SLCO1B1 c.521T→C polymorphism on repaglinide pharmacokinetics persists over a wide dose range.
AIMS
To establish whether the effect of SLCO1B1[encoding organic anion transporting polypeptide 1B1 (OATP1B1)] c.521T→C (p.Val174Ala) polymorphism on the pharmacokinetics of repaglinide is dose-dependent.
METHODS
Twelve healthy volunteers with the SLCO1B1 c.521TT genotype (controls) and eight with the c.521CC genotype ingested a single 0.25-, 0.5-, 1- or 2-mg dose of repaglinide in a dose-escalation study with a wash-out period of ≥1 week.
RESULTS
The mean area under the plasma concentration–time curve from time 0 to infinity (AUC0–∞) of 0.25, 0.5, 1 or 2 mg repaglinide was 82% (95% confidence interval 47, 125), 72% (24, 138), 56% (24, 95) or 108% (59, 171) (P ≤ 0.001) larger in participants with the SLCO1B1 c.521CC genotype than in those with the c.521TT genotype, respectively. Repaglinide peak plasma concentration and AUC0–∞ increased linearly along with repaglinide dose in both genotype groups (r > 0.88, P < 0.001). There was a tendency towards lower blood glucose concentrations after repaglinide administration in the participants with the c.521CC genotype than in those with the c.521TT genotype.
CONCLUSIONS
The effect of SLCO1B1 c.521T→C polymorphism on the pharmacokinetics of repaglinide persists throughout the clinically relevant dose range.
doi:10.1111/j.1365-2125.2008.03287.x
PMCID: PMC2675779  PMID: 18823304
OATP1B1; organic anion transporting polypeptide; pharmacogenetics; pharmacokinetics; repaglinide; SLCO1B1
16.  OATP1B1-related drug–drug and drug–gene interactions as potential risk factors for cerivastatin-induced rhabdomyolysis 
Pharmacogenetics and genomics  2013;23(7):355-364.
Objective
Genetic variation in drug metabolizing enzymes and membrane transporters as well as concomitant drug therapy can modulate the beneficial and the deleterious effects of drugs. We investigated whether patients exhibiting rhabdomyolysis who were taking cerivastatin possess functional genetic variants in SLCO1B1 and whether they were on concomitant medications that inhibit OATP1B1, resulting in accumulation of cerivastatin.
Methods
This study had three components: (a) resequencing the SLCO1B1 gene in 122 patients who developed rhabdomyolysis while on cerivastatin; (b) functional evaluation of the identified SLCO1B1 nonsynonymous variants and haplotypes in in-vitro HEK293/FRT cells stably transfected with pcDNA5/FRT empty vector, SLCO1B1 reference, variants, and haplotypes; and (c) in-vitro screening of 15 drugs commonly used among the rhabdomyolysis cases for inhibition of OATP1B1-mediated uptake of cerivastatin in HEK293/FRT cells stably transfected with reference SLCO1B1.
Results
The resequencing of the SLCO1B1 gene identified 54 variants. In-vitro functional analysis of SLCO1B1 nonsynonymous variants and haplotypes showed that the V174A, R57Q, and P155T variants, a novel frameshift insertion, OATP1B1*14 and OATP1B1*15 haplotype were associated with a significant reduction (P<0.001) in cerivastatin uptake (32, 18, 72, 3.4, 2.1 and 5.7% of reference, respectively). Furthermore, clopidogrel and seven other drugs were shown to inhibit OATP1B1-mediated uptake of cerivastatin.
Conclusion
Reduced function of OATP1B1 related to genetic variation and drug–drug interactions likely contributed to cerivastatin-induced rhabdomyolysis. Although cerivastatin is no longer in clinical use, these findings may translate to related statins and other substrates of OATP1B1.
doi:10.1097/FPC.0b013e3283620c3b
PMCID: PMC3894639  PMID: 23652407
cerivastatin; clopidogrel; OATP1B1; rhabdomyolysis
17.  SLCO2B1 and SLCO1B3 May Determine Time to Progression for Patients Receiving Androgen Deprivation Therapy for Prostate Cancer 
Journal of Clinical Oncology  2011;29(18):2565-2573.
Purpose
Androgen deprivation therapy (ADT), an important treatment for advanced prostate cancer, is highly variable in its effectiveness. We hypothesized that genetic variants of androgen transporter genes, SLCO2B1 and SLCO1B3, may determine time to progression on ADT.
Patients and Methods
A cohort of 538 patients with prostate cancer treated with ADT was genotyped for SLCO2B1 and SLCO1B3 single nucleotide polymorphisms (SNP). The biologic function of a SLCO2B1 coding SNP in transporting androgen was examined through biochemical assays.
Results
Three SNPs in SLCO2B1 were associated with time to progression (TTP) on ADT (P < .05). The differences in median TTP for each of these polymorphisms were about 10 months. The SLCO2B1 genotype, which allows more efficient import of androgen, enhances cell growth and is associated with a shorter TTP on ADT. Patients carrying both SLCO2B1 and SLCO1B3 genotypes, which import androgens more efficiently, exhibited a median 2-year shorter TTP on ADT, demonstrating a gene-gene interaction (Pinteraction = .041).
Conclusion
Genetic variants of SLCO2B1 and SLCO1B3 may function as pharmacogenomic determinants of resistance to ADT in prostate cancer.
doi:10.1200/JCO.2010.31.2405
PMCID: PMC3138634  PMID: 21606417
18.  Prostaglandin Transporter (PGT/SLCO2A1) Protects the Lung from Bleomycin-Induced Fibrosis 
PLoS ONE  2015;10(4):e0123895.
Prostaglandin (PG) E2 exhibits an anti-fibrotic effect in the lung in response to inflammatory reactions and is a high-affinity substrate of PG transporter (SLCO2A1). The present study aimed to evaluate the pathophysiological relevance of SLCO2A1 to bleomycin (BLM)-induced pulmonary fibrosis in mice. Immunohistochemical analysis indicated that Slco2a1 protein was expressed in airway and alveolar type I (ATI) and II (ATII) epithelial cells, and electron-microscopic immunohistochemistry further demonstrated cell surface expression of Slco2a1 in ATI cells in wild type (WT) C57BL/6 mice. PGE2 uptake activity was abrogated in ATI-like cells from Slco2a1-deficient (Slco2a1-/-) mice, which was clearly observed in the cells from WT mice. Furthermore, the PGE2 concentrations in lung tissues were lower in Slco2a1-/- than in WT mice. The pathological relevance of SLCO2A1 was further studied in mouse BLM-induced pulmonary fibrosis models. BLM (1 mg/kg) or vehicle (phosphate buffered saline) was intratracheally injected into WT and Slco2a1-/- mice, and BLM-induced fibrosis was evaluated on day 14. BLM induced more severe fibrosis in Slco2a1-/- than in WT mice, as indicated by thickened interstitial connective tissue and enhanced collagen deposition. PGE2 levels were higher in bronchoalveolar lavage fluid, but lower in lung tissues of Slco2a1-/- mice. Transcriptional upregulation of TGF-β1 was associated with enhanced gene transcriptions of downstream targets including plasminogen activator inhitor-1. Furthermore, Western blot analysis demonstrated a significant activation of protein kinase C (PKC) δ along with a modest activation of Smad3 in lung from Slco2a1-/- mice, suggesting a role of PKCδ associated with TGF-β signaling in aggravated fibrosis in BLM-treated Slco2a1-/- mice. In conclusion, pulmonary PGE2 disposition is largely regulated by SLCO2A1, demonstrating that SLCO2A1 plays a critical role in protecting the lung from BLM-induced fibrosis.
doi:10.1371/journal.pone.0123895
PMCID: PMC4414486  PMID: 25923111
19.  Polymorphisms in folate pathway and pemetrexed treatment outcome in patients with malignant pleural mesothelioma 
Radiology and Oncology  2014;48(2):163-172.
Introduction
A combination of pemetrexed and cisplatin has been shown to improve the outcome in patients with malignant pleural mesothelioma (MPM), however, there is a great heterogeneity in treatment response among patients. The aim of our study was to evaluate the influence of polymorphisms in folate pathway and transporter genes on pemetrexed treatment outcome in Slovenian patients with MPM.
Methods
MPM patients treated with pemetrexed in the course of a prospective randomized clinical trial were genotyped for nineteen polymorphisms in five genes of folate pathway and six transporter genes. Logistic regression was used to assess the influence of polymorphisms on treatment efficacy and toxicity, while Cox regression was used to determine their influence on progression-free and overall survival.
Results
Patients with at least one polymorphic MTHFD1 rs2236225 allele had a significantly lower response rate (p = 0.005; odds ratio [OR] = 0.12; 95% confidence interval [CI] = 0.03−0.54) and shorter progression-free survival (p = 0.032; hazard ratio [HR] = 3.10; 95% CI = 1.10−8.74) than non-carriers. Polymorphisms in transporter genes did not influence survival; however, several were associated with toxicity. Liver toxicity was significantly lower in carriers of polymorphic ABCC2 rs2273697 (p = 0.028; OR = 0.23; 95% CI = 0.06−0.85), SLCO1B1 rs4149056 (p = 0.028; OR = 0.23; 95% CI = 0.06−0.85) and rs11045879 (p = 0.014; OR = 0.18; 95% CI = 0.05−0.71) alleles compared to non-carriers, as well as in patients with SLCO1B1 GCAC haplotype (p = 0.048; OR = 0.17; 95% CI = 0.03−0.98). Gastrointestinal toxicity was much more common in patients with polymorphic ABCC2 rs717620 allele (p = 0.004; OR = 10.67; 95% CI = 2.15−52.85) and ABCC2 CAG haplotype (p = 0.006; OR = 5.67; 95% CI = 1.64−19.66).
Conclusions
MTHFD1 polymorphism affected treatment response and survival, while polymorphisms in ABCC2 and SLCO1B1 transporter genes influenced the risk for toxicity. These polymorphisms could serve as potential markers of pemetrexed treatment outcome in patients with MPM.
doi:10.2478/raon-2013-0086
PMCID: PMC4078035  PMID: 24991206
mesothelioma; pemetrexed; polymorphism; folate pathway; toxicity
20.  Effect of SLCO1B1 genetic polymorphism on the pharmacokinetics of nateglinide 
Aims
Nateglinide is a meglitinide analogue with antidiabetic action. A recent study showed that SLCO1B1 (which codes the OATP1B1 gene, also known as OATP-C, OATP2) is a major determinant which markedly affects the pharmacokinetics of repaglinide. Our objective was to assess the association between single nucleotide polymorphisms (SNPs) of SLCO1B1 and the pharmacokinetics of nateglinide.
Methods
Seventeen healthy volunteers with different SLCO1B1 genotypes (11 with 521TT, four with 521TC and two with 521CC) were enrolled in this study. Each was given a single oral dose of 90 mg nateglinide. Plasma concentrations of nateglinide were measured up to 8 h by HPLC.
Results
The Cmax and AUC(0,∞) of nateglinide were 83% (P = 0.002) and 82% (P = 0.001) higher in the SLCO1B 1521TC subjects (n = 4), and 76% (P = 0.016) and 108% (P = 0.001) higher in the SLCO1B1521CC subjects (n = 2) than in the SLCO1B1521TT subjects (n = 11), respectively. The t1/2 of nateglinide in SLCO1B1521CC subjects was 78% longer than that in 521TT subjects (P = 0.036). The difference in tmax values among the three genotypic groups was not statistically significant.
Conclusions
Our results suggest that OATP1B1-mediated hepatic uptake of nateglinide may be the prior step for its metabolism and elimination. SLCO1B1521T > C SNP might play an important role in the pharmacokinetics of nateglinide.
doi:10.1111/j.1365-2125.2006.02686.x
PMCID: PMC1885174  PMID: 16796707
nateglinide; pharmacokinetics; SLCO1B1 polymorphism
21.  Influence of SLCO1B1 and CYP2C8 gene polymorphisms on rosiglitazone pharmacokinetics in healthy volunteers 
Human Genomics  2008;3(1):7-16.
Polymorphisms in drug transporter genes and/or drug-metabolising enzyme genes may contribute to inter-individual variability in rosiglitazone pharmacokinetics in humans. We sought to determine the joint effects of polymorphisms in the SLCO1B1 drug transporter gene and the cytochrome P450 (CYP) 2C8-metabolising enzyme gene on rosiglitazone pharmacokinetics in healthy volunteers. Healthy Caucasian subjects were prospectively enrolled on the basis of SLCO1B1 521 T > C genotype. Additionally, subjects were genotyped for SLCO1B1 11187 G > A, - 10499 A > C and 388 A > G polymorphisms, and the CYP2C8*3 polymorphism. SLCO1B1 haplotypes and diplotypes were computationally assigned. Rosiglitazone plasma concentrations were determined by high-performance liquid chromatography and analysed using non-compartmental methods. The study population consisted of 26 subjects, with a mean age of 33 ± 9 years, and a mean weight of 66.6 ± 11.7 kg. There were no significant differences in rosiglitazone pharmacokinetic parameters between SLCO1B1 diplotype groups. Subjects with the CYP2C8*1/*3 genotype (n = 7), however, had significantly lower rosiglitazone area under the plasma concentration-time curve (AUC) and significantly higher rosiglitazone oral clearance, compared with CYP2C8 wild-type homozygotes (n = 19). Stepwise linear regression analysis revealed that CYP2C8 genotype (p = 0.006) and weight (p = 0.022) were significant predictors of rosiglitazone AUC (overall p = 0.002; R2 = 41.6 per cent). We concluded that polymorphisms in the CYP2C8 drug-metabolising enzyme gene, but not the SLCO1B1 drug transporter gene, significantly influence rosiglitazone disposition in humans. Future studies examining the influence of CYP2C8 genotypes and haplotypes on thiazolidinedione disposition and response in patients with type 2 diabetes are warranted.
doi:10.1186/1479-7364-3-1-7
PMCID: PMC3525178  PMID: 19129086
rosiglitazone; thiazolidinedione; pharmacokinetic; pharmacogenetic; CYP2C8; SLCO1B1
22.  Potent inhibition of rhabdoid tumor cells by combination of flavopiridol and 4OH-tamoxifen 
BMC Cancer  2010;10:634.
Background
Rhabdoid Tumors (RTs) are highly aggressive pediatric malignancies with poor prognosis. There are currently no standard or effective treatments for RTs in part because treatments are not designed to specifically target these tumors. Our previous studies indicated that targeting the cyclin/cdk pathway is a novel therapeutic strategy for RTs and that a pan-cdk inhibitor, flavopiridol, inhibits RT growth. Since the toxicities and narrow window of activity associated with flavopiridol may limit its clinical use, we tested the effect of combining flavopiridol with 4-hydroxy-Tamoxifen (4OH-Tam) in order to reduce the concentration of flavopiridol needed for inhibition of RTs.
Methods
The effects of flavopiridol, 4OH-Tam, and their combination on RT cell cycle regulation and apoptosis were assessed by: i) cell survival assays, ii) FACS analysis, iii) caspase activity assays, and iv) immunoblot analysis. Furthermore, the role of p53 in flavopiridol- and 4OH-Tam-mediated induction of cell cycle arrest and apoptosis was characterized using RNA interference (siRNA) analysis. The effect of p53 on flavopiridol-mediated induction of caspases 2, 3, 8 and 9 was also determined.
Results
We found that the combination of flavopiridol and 4OH-Tam potently inhibited the growth of RT cells. Low nanomolar concentrations of flavopiridol induced G2 arrest, which was correlated to down-modulation of cyclin B1 and up-regulation of p53. Addition of 4OH-Tam did not affect flavopiridol-mediated G2 arrest, but enhanced caspase 3,7-mediated apoptosis induced by the drug. Abrogation of p53 by siRNA abolished flavopiridol-induced G2 arrest, but enhanced flavopiridol- (but not 4OH-Tam-) mediated apoptosis, by enhancing caspase 2 and 3 activities.
Conclusions
Combining flavopiridol with 4OH-Tam potently inhibited the growth of RT cells by increasing the ability of either drug alone to induce caspases 2 and 3 thereby causing apoptosis. The potency of flavopiridol was enhanced by abrogation of p53. Our results warrant further studies investigating the combinatorial effects of flavopiridol and 4OH-Tam as a novel therapeutic strategy for RTs and other tumors that have been shown to respond to flavopiridol.
doi:10.1186/1471-2407-10-634
PMCID: PMC2998513  PMID: 21092078
23.  A Pharmacokinetic/Pharmacodynamic Model of Tumor Lysis Syndrome in Chronic Lymphocytic Leukemia Patients Treated with Flavopiridol 
Purpose
Flavopiridol, the first clinically evaluated cyclin dependent kinase inhibitor, demonstrates activity in patients with refractory chronic lymphocytic leukemia, but prevalent and unpredictable tumor lysis syndrome (TLS) presents a major barrier to its broad clinical use. The purpose of this study was to investigate the relationships between pretreatment risk factors, drug pharmacokinetics, and TLS.
Experimental Design
A population pharmacokinetic/pharmacodynamic model linking drug exposure and TLS was developed. Plasma data of flavopiridol and its glucuronide metabolite (flavo-G) were obtained from 111 patients treated in early phase trials with frequent sampling following initial and/or escalated doses. TLS grading was modeled with logistic regression as a pharmacodynamic endpoint. Demographics, baseline disease status, and blood chemistry variables were evaluated as covariates.
Results
Gender was the most significant pharmacokinetic covariate, with females displaying higher flavo-G exposure than males. Glucuronide metabolite exposure was predictive of TLS occurrence, and bulky lymphadenopathy was identified as a significant covariate on TLS probability. The estimated probability of TLS occurrence in patients with baseline bulky lymphadenopathy < 10 cm or > 10 cm during the first two treatments was 0.111 (SE% 13.0%) and 0.265, (SE% 17.9%) respectively, when flavo-G area under the plasma concentration vs. time curve was at its median value in whole patient group.
Conclusions
This is the first population pharmacokinetic/pharmacodynamic model of TLS. Further work is needed to explore potential mechanisms and to determine if the associations between TLS, gender and glucuronide metabolites are relevant in CLL patients treated with other cyclin dependent kinase inhibitors.
doi:10.1158/1078-0432.CCR-12-1092
PMCID: PMC3845832  PMID: 23300276
chronic lymphocytic leukemia; flavopiridol; tumor lysis syndrome; population pharmacokinetics; glucuronide metabolite; logistic regression model
24.  Targeted Disruption of Murine Organic Anion-Transporting Polypeptide 1b2 (oatp1b2/Slco1b2) Significantly Alters Disposition of Prototypical Drug Substrates Pravastatin and Rifampin 
Molecular pharmacology  2008;74(2):320-329.
Organic anion transporting polypeptide (OATP) 1B1 and 1B3 are widely acknowledged as important and rate-limiting to the hepatic uptake of many drugs in clinical use. Accordingly, to better understand the in vivo relevance of OATP1B transporters, targeted disruption of murine Slco1b2 gene was carried out. Interestingly, Slco1b2−/− mice were fertile, developed normally, and did not exhibit any overt phenotypic abnormalities. We confirmed the loss of Oatp1b2 expression in liver using real-time PCR, Western Blot analysis and immunohistochemistry. Oatp1a4 and Oatp2b1, but not Oatp1a1 expression was greater in female Slco1b2−/− mice, but expression of other non-oatp transporters did not significantly differ between wildtype and Slco1b2−/− males. Total bilirubin level was elevated by 2-fold in the Slco1b2−/− mice despite that liver enzymes ALT and AST were normal. Pharmacological characterization was carried out using two prototypical substrates of human OATP1B1 and 1B3, rifampin and pravastatin. After a single intravenous dose of rifampin (1mg/kg), a 1.7-fold increase in plasma AUC was observed while the liver-to-plasma ratio was reduced by 5-fold, and nearly 8-fold when assessed at steady -state conditions after 24 hours of continuous subcutaneous (SC) infusion in Slco1b2−/− mice. Similarly, continuous SC-infusion at low dose rate (8 μg/hr) or high dose rate (32 μg/hr) pravastatin resulted in a 4-fold lower liver-plasma ratio in the in Slco1b2−/− mice. This is the first report of altered drug disposition profile in the Slco1b2 knockout mice and suggests the utility of this model for understanding the in vivo role of hepatic OATP transporters in drug disposition.
doi:10.1124/mol.108.046458
PMCID: PMC2562886  PMID: 18413659
25.  Synergistic interaction between genetics and disease on pravastatin disposition 
Journal of hepatology  2014;61(1):139-147.
Background & Aims
A genome wide association study and multiple pharmacogenetic studies have implicated the hepatic uptake transporter organic anion transporting polypeptide-1B1 (OATP1B1) in the pharmacokinetics and musculoskeletal toxicity of statin drugs. Other OATP uptake transporters can participate in the transport of pravastatin, partially compensating for the loss of OATP1B1 in patients carrying the polymorphism. Nonalcoholic steatohepatitis (NASH) in humans and in a diet-induced rodent model alter the expression of multiple OATP transporters.
Methods
To determine how genetic alteration in one Oatp transporter can interact with NASH-associated changes in Oatp expression we measured the disposition of intravenously administered pravastatin in Slco1b2 knockout (Slco1b2−/−) and wild-type (WT) mice fed either a control or a methionine and choline deficient (MCD) diet to induce NASH.
Results
Genetic loss of Oatp1b2, the rodent ortholog of human OATP1B transporters, caused a modest increase in pravastatin plasma concentrations in mice with healthy livers. Although a diet-induced model of NASH decreased the expression of multiple hepatic Oatp transporters, it did not alter the disposition of pravastatin compared to WT control mice. In contrast, the combination of NASH-associated decrease in compensatory Oatp transporters and Oatp1b2 genetic loss caused a synergistic increase in plasma area under the curve (AUC) and tissue concentrations in kidney and muscle.
Conclusions
Our data show that NASH alters the expression of multiple hepatic uptake transporters which, due to overlapping substrate specificity among the OATP transporters, may combine with the pharmacogenetic loss of OATP1B1 to increase the risk of statin-induced adverse drug reactions.
doi:10.1016/j.jhep.2014.02.021
PMCID: PMC4065643  PMID: 24613363
Non-alcoholic steatohepatitis; statin; myopathy; adverse drug reaction

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