Issey Takehara1,2, Takashi Yoshikado3,4, Keiko Ishigame4, Daiki Mori2, Ken-Ichi Furihata5, Nobuaki Watanabe6, Osamu Ando6, Kazuya Maeda2, Yuichi Sugiyama4, Hiroyuki Kusuhara7. 1. Biomarker Department, Daiichi Sankyo Co. Ltd., Tokyo, Japan. 2. Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. 3. Laboratory of Clinical Pharmacology, Yokohama University of Pharmacy, 601 Matano-cho, Totsuka-ku, Yokohama-shi, Kanagawa, 245-0066, Japan. 4. Sugiyama Laboratory, RIKEN Innovation Center, RIKEN, Yokohama, Japan. 5. P-One Clinic, Keikokai Medical Corp, Tokyo, Japan. 6. Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan. 7. Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. kusuhara@mol.f.u-tokyo.ac.jp.
Abstract
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 AUC0-24h of atorvastatin was reasonably correlated with that of pitavastatin (r2 = 0.73) and with the AUC0-4h of fluvastatin (r2 = 0.62) and sufficiently with the AUC0-24h of rosuvastatin (r2 = 0.32). The AUC0-24h of GCDCA-S was reasonably correlated with those of direct bilirubin (r2 = 0.74) and coproporphyrin I (r2 = 0.78), and sufficiently with that of total bilirubin (r2 = 0.30). The AUC0-24h of GCDCA-S, direct bilirubin, and coproporphyrin I were reasonably correlated with that of atorvastatin (r2 = 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.
RCT Entities:
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 AUC0-24h of atorvastatin was reasonably correlated with that of pitavastatin (r2 = 0.73) and with the AUC0-4h of fluvastatin (r2 = 0.62) and sufficiently with the AUC0-24h of rosuvastatin (r2 = 0.32). The AUC0-24h of GCDCA-S was reasonably correlated with those of direct bilirubin (r2 = 0.74) and coproporphyrin I (r2 = 0.78), and sufficiently with that of total bilirubin (r2 = 0.30). The AUC0-24h of GCDCA-S, direct bilirubin, and coproporphyrin I were reasonably correlated with that of atorvastatin (r2 = 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.
Authors: S Ito; H Kusuhara; Y Kumagai; Y Moriyama; K Inoue; T Kondo; H Nakayama; S Horita; K Tanabe; H Yuasa; Y Sugiyama Journal: Clin Pharmacol Ther Date: 2012-10-10 Impact factor: 6.875
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