PT - JOURNAL ARTICLE AU - Hong Shen AU - Weiqi Chen AU - Dieter M Drexler AU - Sandhya Mandlekar AU - Vinay K Holenarsipur AU - Eric E Shields AU - Robert Langish AU - Kurex Sidik AU - Jinping Gan AU - W Griffith Humphreys AU - Punit Marathe AU - Yurong Lai TI - Comparative Evaluation of Plasma Bile Acids, Dehydroepiandrosterone Sulfate, Hexadecanedioate and Tetradecanedioate with Coproporphyrins I and III as Markers of OATP Inhibition in Healthy Subjects AID - 10.1124/dmd.117.075531 DP - 2017 Jan 01 TA - Drug Metabolism and Disposition PG - dmd.117.075531 4099 - http://dmd.aspetjournals.org/content/early/2017/06/02/dmd.117.075531.short 4100 - http://dmd.aspetjournals.org/content/early/2017/06/02/dmd.117.075531.full AB - Multiple endogenous compounds have been proposed as candidate biomarkers to monitor organic anion transporting polypeptide (OATP) function in preclinical species or humans. Recently we have demonstrated that coproporphyrins (CPs) I and III are appropriate clinical markers to evaluate OATP inhibition and recapitulate clinical drug-drug interactions (DDIs). In the present studies, we investigated bile acids (BAs), dehydroepiandrosterone sulfate (DHEAS), hexadecanedioate (HDA), and tetradecanedioate (TDA) in plasma as endogenous probes for OATP inhibition and compared these candidate probes to CPs. All probes were determined in samples from a single study that examined their behavior and their association with rosuvastatin (RSV) pharmacokinetics after administration of an OATP inhibitor rifampin (RIF) in healthy subjects. Among endogenous probes examined, RIF significantly increased Cmax and AUC(0-24h) of fatty acids HDA and TDA by 2.2- to 3.2-fold. For the 13 bile acids in plasma examined, no statistically significant changes were detected between treatments. Changes in plasma 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. Collectively, these results re-confirmed that CPs are novel biomarkers that are suitable for clinical use. In addition, HDA and TDA are useful for OATP functional assessment. Since these endogenous markers can be monitored in conjunction with pharmacokinetics analysis, the CPs and fatty acid dicarboxylates, either alone or in combination offer promise of earlier diagnosis and risk stratification for OATP-mediated DDIs.