Epacadostat (EPAC) is a first-in-class, orally active inhibitor of the enzyme indoleamine 2,3-dioxygenase 1 (IDO1) and has demonstrated promising clinical activity. In humans, three major plasma metabolites were identified: M9 (a glucuronide-conjugate), M11 (a gut microbiota metabolite), and M12 (a secondary metabolite formed from M11). It is proposed that the biliary excretion of M9, the most abundant metabolite, leads to the enterohepatic circulation of EPAC suggested by the human pharmacokinetics of EPAC. The in vitro interactions of EPAC and its major metabolites with major drug transporters involved in drug absorption and disposition were evaluated using various in vitro systems. EPAC is a substrate for efflux transporters, P-gp and BCRP, but not a substrate for hepatic uptake transporters, OATP1B1 and OATP1B3. The low permeability of M9 suggests an essential role for transporters in its disposition. M9 is likely excreted from hepatocytes into bile via MRP2 and BCRP, excreted into blood via MRP3, and transported from blood back into hepatocytes via OATP1B1 and OATP1B3. M11 and M12 are not substrates for P-gp, OATP1B1 or OATP1B3, and M11, but not M12, is a substrate for BCRP. With respect to inhibition of drug transporters, the potential of EPAC, M9, M11, and M12 to cause clinical DDIs via inhibition of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2 was estimated to be low. The current investigation underlines the importance of metabolite-transporter interactions in the disposition of clinically relevant metabolites, which may have implications for the pharmacokinetics and drug interactions of parent drugs.
- drug-drug interactions
- efflux transporters (P-gp, BCRP, MRP, MATE, BSEP, etc)
- metabolite disposition
- Transporter-mediated drug/metabolite disposition
- Uptake transporters (OATP, OAT, OCT, PEPT, MCT, NTCP, ASBT, etc.)
- The American Society for Pharmacology and Experimental Therapeutics