Comparative Study of the Dose-Dependence of OATP1B Inhibition by Rifampicin Using Probe Drugs and Endogenous Substrates in Healthy Volunteers.

Purpose: To evaluate association of the dose-dependent effect of rifampicin, an OATP1B inhibitor, on the plasma concentration-time profiles among OATP1B substrates drugs and endogenous substrates.

Methods: Eight healthy volunteers received atorvastatin (1 mg), pitavastatin (0.2 mg), rosuvastatin (0.5 mg), and fluvastatin (2 mg) alone or with rifampicin (300 or 600 mg) in a crossover fashion. The plasma concentrations of these OATP1B probe drugs, total and direct bilirubin, glycochenodeoxycholate-3-sulfate (GCDCA-S), and coproporphyrin I, were determined.

Results: The most striking effect of 600 mg rifampicin was on atorvastatin (6.0-times increase) and GCDCA-S (10-times increase). The AUC of atorvastatin was reasonably correlated with that of pitavastatin (r = 0.73) and with the AUC of fluvastatin (r = 0.62) and sufficiently with the AUC of rosuvastatin (r = 0.32). The AUC of GCDCA-S was reasonably correlated with those of direct bilirubin (r = 0.74) and coproporphyrin I (r = 0.78), and sufficiently with that of total bilirubin (r = 0.30). The AUC of GCDCA-S, direct bilirubin, and coproporphyrin I were reasonably correlated with that of atorvastatin (r = 0.48-0.70) [corrected].

Conclusion: These results suggest that direct bilirubin, GCDCA-S, and coproporphyrin I are promising surrogate probes for the quantitative assessment of potential OATP1B-mediated DDI.