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1.  Prediction of Solubility and Permeability Class Membership: Provisional BCS Classification of the World’s Top Oral Drugs 
The AAPS Journal  2009;11(4):740-746.
The Biopharmaceutics Classification System (BCS) categorizes drugs into one of four biopharmaceutical classes according to their water solubility and membrane permeability characteristics and broadly allows the prediction of the rate-limiting step in the intestinal absorption process following oral administration. Since its introduction in 1995, the BCS has generated remarkable impact on the global pharmaceutical sciences arena, in drug discovery, development, and regulation, and extensive validation/discussion/extension of the BCS is continuously published in the literature. The BCS has been effectively implanted by drug regulatory agencies around the world in setting bioavailability/bioequivalence standards for immediate-release (IR) oral drug product approval. In this review, we describe the BCS scientific framework and impact on regulatory practice of oral drug products and review the provisional BCS classification of the top drugs on the global market. The Biopharmaceutical Drug Disposition Classification System and its association with the BCS are discussed as well. One notable finding of the provisional BCS classification is that the clinical performance of the majority of approved IR oral drug products essential for human health can be assured with an in vitro dissolution test, rather than empirical in vivo human studies.
doi:10.1208/s12248-009-9144-x
PMCID: PMC2782078  PMID: 19876745
BA/BE; biopharmaceutics classification system; biowaiver; intestinal absorption; molecular biopharmaceutics; oral drug product
2.  The H2 Receptor Antagonist Nizatidine is a P-Glycoprotein Substrate: Characterization of its Intestinal Epithelial Cell Efflux Transport 
The AAPS Journal  2009;11(2):205-213.
The aim of this study was to elucidate the intestinal epithelial cell efflux transport processes that are involved in the intestinal transport of the H2 receptor antagonist nizatidine. The intestinal epithelial efflux transport mechanisms of nizatidine were investigated and characterized across Caco-2 cell monolayers, in the concentration range 0.05–10 mM in both apical–basolateral (AP–BL) and BL–AP directions, and the transport constants of P-glycoprotein (P-gp) efflux activity were calculated. The concentration-dependent effects of various P-gp (verapamil, quinidine, erythromycin, ketoconazole, and cyclosporine A), multidrug resistant-associated protein 2 (MRP2; MK-571, probenecid, indomethacin, and p-aminohipuric acid), and breast cancer resistance protein (BCRP; Fumitremorgin C) inhibitors on nizatidine bidirectional transport were examined. Nizatidine exhibited 7.7-fold higher BL–AP than AP–BL Caco-2 permeability, indicative of net mucosal secretion. All P-gp inhibitors investigated displayed concentration-dependent inhibition on nizatidine secretion in both directions. The IC50 of verapamil on nizatidine P-gp secretion was 1.2 × 10−2 mM. In the absence of inhibitors, nizatidine displayed concentration-dependent secretion, with one saturable (Jmax = 5.7 × 10−3 nmol∙cm−2∙s−1 and Km = 2.2 mM) and one nonsaturable component (Kd = 7 × 10−4 μL∙cm−2∙s−1). Under complete P-gp inhibition, nizatidine exhibited linear secretory flux, with a slope similar to the nonsaturable component. Vmax and Km estimated for nizatidine P-gp-mediated secretion were 4 × 10−3 nmol∙cm−2∙s−1 and 1.2 mM, respectively. No effect was obtained with the MRP2 or the BCRP inhibitors. Being a drug commonly used in pediatrics, adults, and elderly, nizatidine susceptibility to efflux transport by P-gp revealed in this paper may be of significance in its absorption, distribution, and clearance, as well as possible drug–drug interactions.
doi:10.1208/s12248-009-9092-5
PMCID: PMC2691456  PMID: 19319690
BCS class III drugs; caco-2 permeability; efflux transporters; intestinal absorption; nizatidine; P-glycoprotein
3.  Summary Workshop Report: Bioequivalence, Biopharmaceutics Classification System, and Beyond 
The AAPS Journal  2008;10(2):373-379.
The workshop “Bioequivalence, Biopharmaceutics Classification System, and Beyond” was held May 21–23, 2007 in North Bethesda, MD, USA. This workshop provided an opportunity for pharmaceutical scientists to discuss the FDA guidance on the Biopharmaceutics Classification System (BCS), bioequivalence of oral products, and related FDA initiatives such as the FDA Critical Path Initiative. The objective of this Summary Workshop Report is to document the main points from this workshop. Key highlights of the workshop were (a) the described granting of over a dozen BCS-based biowaivers by the FDA for Class I drugs whose formulations exhibit rapid dissolution, (b) continued scientific support for biowaivers for Class III compounds whose formulations exhibit very rapid dissolution, (c) scientific support for a number of permeability methodologies to assess BCS permeability class, (d) utilization of BCS in pharmaceutical research and development, and (e) scientific progress in in vitro dissolution methods to predict dosage form performance.
doi:10.1208/s12248-008-9040-9
PMCID: PMC2751390  PMID: 18679807
bioavailability; bioequivalence; biopharmaceutics classification system (BCS); oral absorption; permeability; regulatory science; solubility
4.  Transporter and ion channel gene expression after caco-2 cell differentiation using 2 different microarray technologies 
The AAPS Journal  2004;6(3):35-44.
mRNA expression profiles had previously been measured in Caco-2 cells (human colonic carcinoma cells) using either custom-designed spotted oligonucleotide arrays or Affymetrix GeneChip oligonucleotide arrays. The Caco-2 cells used were from different clones and were examined under slightly different culture conditions commonly encountered when Caco-2 cells are used as a model tissue for studying intestinal transport and metabolism in different laboratories. In this study, we compared gene expression profiles of Caco-2 cells generated with different arrays to assess the validity of conclusions derived from the 2 independent studies, with a focus on changes in transporter and ion channel mRNA expression levels on Caco-2 cell differentiation. Significant changes in expression levels upon differentiation were observed with 78 genes, with probes common to both arrays. Of these, 18 genes were upregulated and 36 genes were downregulated. The 2 arrays yielded discrepant results for 24 genes, showing significant changes upon differentiation. The results from the 2 arrays correlated well for genes expressed above average levels (r=0.75,P<0.01, n=25) and poorly for genes expressed at low levels (r=0.08,P>0.05, n=25). Overall correlation across the 2 platforms wasr=0.45 (P<0.01) for the 78 genes, with similar results from both arrays. Despite differences in experimental conditions and array technology, similar results were obtained for most genes.
doi:10.1208/aapsj060321
PMCID: PMC2751246  PMID: 15760106
microarrays; Caco-2 cells; transporter; ion channel; platform comparison

Results 1-4 (4)