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Hepatic uptake by OATP1B1 and OATP1B3 represents the rate-determining process for clearance of many drugs, and the transporters can serve as loci for drug interactions. In the present study, we have investigated the potential for plasma concentrations of coproporphyrins (CPs) I and III, bilirubin (BILI), bile acids (BAs), dehydroepiandrosterone sulfate (DHEAS), hexadecanedioate (HDA), and tetradecanedioate (TDA) to serve as endogenous probes for OATP1B inhibition in healthy Asian subjects (n = 12).
Among endogenous probes examined, rifampin (RIF) significantly increased Cmax and AUC of CP I and CP III by 3.3- to 6.5-fold. It also increased Cmax and AUC of HDA and TDA by 2.2- to 3.2-fold. These changes are similar to that of rosuvastatin (RSV) AUC (5.0-fold). For the 13 bile acids in plasma examined, no statistically significant changes were detected between treatments. Changes in plasma BILI and DHEAS did not correlate with OATP1B inhibition by RIF.
Based on the magnitude of effect sizes for the endogenous compounds that demonstrated significant changes from baseline over inter-individual variations, the overall rank order for the AUC change was found to be CP I > CP III > HDA ≈ TDA ≈ RSV >> BAs ≈ BILI ≈ DHEAS. In an additional study conducted in black, white and Hispanic subjects (n = 16), the Cmax and AUC of CP I and CP III were increased 2.8- to 3.7-fold by RIF (a single oral dose of 600 mg), consistent with the values observed previously in Asian population.
Furthermore, co-administration of itraconazole and diltiazem, two BMS compounds with minimal potential to inhibit OATP1B, did not significantly increase plasma CP concentrations relative to predose levels. Collectively, these results suggest that CPs are novel biomarkers that are suitable for clinical use.
Dr. Hong Shen
Bristol- Myers Squibb
Dr. Shen currently is a Principal Scientist in the Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Company, where he researches drug transporter activities and provides preclinical DMPK support for multiple drug discovery and development projects.
He earned his doctorate under the supervision of David Smith of the University of Michigan, where his research focused on the role of PEPT2 transporter in drug renal tubular reabsorption and brain penetration. His areas of expertise in DMPK include drug transporters, drug-drug interactions, and PK/PD modeling.
His research is focused towards mechanistic-based approaches to explain the handling of drugs, metabolites and endogenous biomarkers within eliminating organs, namely the liver and kidney, via the examination of relevant processes of transport and metabolism. Dr. Shen has published over 50 original articles and chapters. He was the recipient of the James R. Gillette Drug Metabolism and Pharmacokinetics Awards selected by the Drug Metabolism Division of ASPET in 2001 and 2007.
He currently is a committee member of the Delaware Valley Drug Metabolism Discussion Group (DVDMDG), AAPS Drug Transporter Focus Group, International Transporter Consortium (ITC) Clinical Probe Drugs and Endogenous Biomarkers Working Group, and IQ Transporter Working Group.
Organizer: Optivia Biotechnology Inc.
Time: Thursday, Feb 15, 2018 10:00 AM - 11:30 AM PDT