| Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Outline of Final Research Achievements |
The aim of the present study was to establish a physiologically-based pharmacokinetic model for coproporphyrin I (CP-I), a biomarker supporting the prediction of drug-drug interactions (DDIs) involving hepatic organic anion transporting polypeptide 1Bs (OATP1Bs), using clinical DDI data with an OATP1Bs inhibitor rifampicin (300 and 600 mg, orally). The in vivo inhibition constants of rifampicin used as initial input parameters for OATP1Bs (Ki,u,OATP1Bs) and multidrug resistance-associated protein 2-mediated biliary excretion were estimated as 0.23 and 0.87 μM, respectively. Ki,u,OATP1Bs values optimized by nonlinear least-squares fitting were ~0.5-fold of the initial value. It was determined that the blood concentration-time profiles of four statins were well-predicted using corrected individual Ki,u,OATP1B values (ratio of in vitro Ki,u(statin)/ in vitro Ki,u(CP-I)). In conclusion, PBPK modeling of CP-I supports dynamic prediction of OATP1Bs-mediated DDIs.
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