Plasma and urinary CP I and CP III concentrations in chimeric mice with human hepatocytes after rifampicin administration

The interest in transporter‐mediated drug interactions has been increasing in the field of drug development. In this study, we measured the plasma and urinary concentrations of coproporphyrin (CP) I and CP III as endogenous substrates for organic anion‐transporting polypeptide (OATP) using chimeric mice with human hepatocytes (PXB mice) and examined the influence of an OATP inhibitor, rifampicin (RIF). CP I and CP III were actively taken up intracellularly, and RIF inhibited the uptake in a concentration‐dependent manner for both CP I and CP III in human hepatocytes (PXB‐cells). Single doses of RIF at 10 and 30 mg/kg were orally or intravenously administered to PXB mice and wild‐type ICR mice. Plasma concentrations (AUC0‐8h) of CP I increased in both mice. However, a marked increase in CP III was only observed in ICR mice, after intravenous administration of RIF at 30 mg/kg. The IC50 values of RIF for intracellular CP I/III uptake and the unbound plasma concentrations of RIF suggested that the increase in plasma CP I is associated with the exposure of RIF to OATPs. The 24‐h cumulative urinary excretions of CP I and CP III increased in both mice, but more markedly in PXB mice. Thus, RIF increased the plasma and urinary concentrations of CP I and CP III in the mice, as reported in humans, and CP I may be a more sensitive biomarker of OATP‐mediated drug interactions in PXB mice. Plasma concentration‐time curves of CP I (A, B) and CP III (C, D) after a single oral or intravenous administration of rifampicin to male PXB mice. Plasma concentrations (AUC0‐8h) in CP I increased markedly with both administrations, but not in CP III.