Inhibition of organic anion-transporting polypeptide (OATP)1B function can lead to serious clinical drug-drug interactions (DDIs), thus a thorough evaluation of the potential for this type of interaction must be completed during drug development. Therefore, sensitive and specific biomarkers for OATP function that could be used in conjunction with clinical studies are currently in demand. In the present study, preclinical evaluations were conducted to characterize the suitability of coproporphyrins (CPs) I and III as markers of hepatic OATP functional activity. Active uptake of CPs I and III was observed in human embryonic kidney (HEK) 293 cells singly expressing human OATP1B1 (hOATP1B1), hOATP1B3, cynomolgus monkey OATP1B1 (cOATP1B1), or cOATP1B3, as well as human and monkey hepatocytes. Cyclosporin A (CsA; 100 mg/kg, oral) markedly increased the area under the plasma concentration curves (AUCs) of CPs I and III by 2.6- and 5.2-fold, while rifampin (RIF, 15 mg/kg, oral) increased the AUCs by 2.7- and 3.6-fold, respectively. As the systemic exposure increased, the excretion of both isomers in urine rose (1.6- to 4.3-fold) in monkeys. In agreement with this finding, AUC of rosuvastatin (RSV) in cynomolgus monkeys increased when OATP1B inhibitors were co-administered. In Oatp1a/1b gene cluster knockout (Oatp1a/1b-/- KO) mice, CPs in plasma and urine were significantly increased compared to wild-type animals (WT) (7.1- to 18.4-fold; p < 0.001), which were also in agreement with the changes in plasma RSV exposure (14.6-fold increase). We conclude that CPs I and III in plasma and urine are novel endogenous biomarkers reflecting hepatic OATP function and the measurements have the potential to be incorporated into the design of early clinical evaluation.
- The American Society for Pharmacology and Experimental Therapeutics