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The aim of the present study was to establish a physiologically based pharmacokinetic (PBPK) model for coproporphyrin I (CP‐I), a biomarker supporting the prediction of drug‐drug interactions ( DDI s) involving hepatic organic anion transporting polypeptide 1 B  ( OATP 1 B ), using clinical  DDI  data with an  OATP 1 B  inhibitor rifampicin (300 and 600 mg, orally). The  in vivo  inhibition constants of rifampicin used as initial input parameters for  OATP 1 B s ( K  i,u,OATP1Bs ) and multidrug resistance‐associated protein two‐mediated biliary excretion were estimated as 0.23 and 0.87 μM, respectively, from previous reports. Sensitivity analysis demonstrated that the  K  i,u,OATP1Bs  and biosynthesis rate of CP‐I affected the magnitude of the interaction.  K  i,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  K  i,u,OATP1B  values (ratio of  in vitro K  i,u(statin) / in vitro K  i,u(CP‐I) ). In conclusion, PBPK modeling of CP‐I supports dynamic prediction of OATP1B‐mediated DDIs.

PBPK Modeling of Coproporphyrin I as an Endogenous Biomarker for Drug Interactions Involving Inhibition of Hepatic OATP1B1 and OATP1B3