Comparative Evaluation of Plasma Bile Acids, Dehydroepiandrosterone Sulfate, Hexadecanedioate, and Tetradecanedioate with Coproporphyrins I and III as Markers of OATP Inhibition in Healthy Subjects

Abstract

Multiple endogenous compounds have been proposed as candidate biomarkers to monitor organic anion transporting polypeptide (OATP) function in preclinical species or humans. Previously, we 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 study, 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 maximum plasma concentration () and area under the concentration-time curve (AUC) 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. On the basis of the magnitude of effects for the endogenous compounds that demonstrated significant changes from baseline over interindividual variations, the overall rank order for the AUC change was found to be CP I > CP III > HDA ≈ TDA ≈ RSV > > BAs. Collectively, these results reconfirmed that CPs are novel biomarkers 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.

Positron Emission Tomography Imaging of [11C]Rosuvastatin Hepatic Concentrations and Hepatobiliary Transport in Humans in the Absence and Presence of Cyclosporin A

“…Therefore, in the RSV‐RIF study, RIF likely affected the first‐pass hepatic extraction of RSV resulting in a bigger increase in RSV plasma concentration. The percent change in plasma concentrations of CPI, CPIII, TBILI, and DBILI in our study are comparable to those observed in humans following RIF administration and cynomolgus monkeys after CsA administration (100 mg/kg p.o.) .…”

Effect of OATP1B1/1B3 Inhibitor GDC‐0810 on the Pharmacokinetics of Pravastatin and Coproporphyrin I/III in Healthy Female Subjects

“…A 5‐ to 6‐fold increase in concentration of coproporphyrin I and III was observed after administration of rifampin (as a strong OATP1B inhibitor in humans), suggesting their utility in capturing potent DDIs mediated by OATP1B1/1B3 inhibition. In a study with healthy subjects, Shen et al investigated bile acids, dehydroepiandrosterone sulfate, hexadecanedioate, and tetradecanedioate in plasma as endogenous biomarkers (probes) for OATP inhibition compared with coproporphyrin I and III. The results demonstrated that coproporphyrins I and III were more appropriate as clinical markers to evaluate OATP inhibition compared with other potential endogenous biomarkers.…”

Dose‐Dependent Inhibition of OATP1B by Rifampicin in Healthy Volunteers: Comprehensive Evaluation of Candidate Biomarkers and OATP1B Probe Drugs

“…As expected, potent OATP1B inhibitors, such as cyclosporine A and rifampicin, have been shown to increase (2‐fold to 16‐fold) the area under the plasma concentration‐time curve (AUC) of OATP1B substrate drugs (UW Drug Interaction Database Program, https://www.druginteractioninfo.org/). We and other groups have demonstrated significant increases in the plasma concentrations of endogenous substrates such as bilirubins, coproporphyrins, amidated and nonamidated bile acids (including glucuronide and sulfate conjugates), and dicarboxylates following a single dose of cyclosporine A, rifampicin, and selected NCEs with OATP1B inhibition potential . Furthermore, the plasma concentrations of some of these endogenous substrates were associated with SLCO1B1 genotype, as those of the statins were .…”

“…We and other groups have demonstrated significant increases in the plasma concentrations of endogenous substrates such as bilirubins, coproporphyrins, amidated and nonamidated bile acids (including glucuronide and sulfate conjugates), and dicarboxylates following a single dose of cyclosporine A, rifampicin, and selected NCEs with OATP1B inhibition potential. [10][11][12][13][14][15][16] Furthermore, the plasma concentrations of some of these endogenous substrates were associated with SLCO1B1 genotype, as those of the statins were. 13,14,17 These cumulative data indicate that endogenous substrates could be used to support OATP1B subject phenotyping and DDI risk assessment.…”