Background: Opicapone is a high-affinity and long-acting third generation nitrocatechol COMT inhibitor for adjunctive therapy in levodopa-treated Parkinsons disease patients.
Objectives: Evaluate the effect of opicapone, a third generation COMT inhibitor, on metabolic enzymes and drug transporters in vitro to anticipate potential in vivo drug-drug interactions.
Methods: To assess the potential of opicapone to inhibit cytochrome P450, the rate of metabolite formation from selective CYP marker substrates by pooled human liver microsomes was measured in the presence of six concentrations (0, 0.03, 0.1, 0.3, 3 and 10 µg/mL) of opicapone. Opicapone was evaluated as substrate and/or inhibitors of SLC transporters OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1 and MATE2-K and of human ATP-binding cassette (ABC) transportes, P-gp, BCRP and BSEP, using vesicles or cell-lines overexpressing each transporters. The binding of [14C]-opicapone to human plasma was determined at the concentration of 0.3, 3 and 30 µg/ml.
Results: When tested against P450 cytochromes (CYP), opicapone were reversible inhibitors of CYP2C8 (IC50, 3.6 µg/ml) and CYP2C9 (IC50, 9.6 µg/ml, respectively). No metabolism dependent inhibition by opicapone was observed for any of the other tested CYPs. Opicapone was a substrate for the breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) efflux transporters and for the organic anion transporting polypeptide transporter (OATP1B3). Opicapone showed moderate inhibition of bile salt export pump (BSEP), and organic anionic transporters (OAT1 and OAT3), but inhibited OATP1B1 and OATP1B3 at lower concentrations (IC50 values of 0.45 and 1.4 µg/ml, respectively). However, when the 99.9% binding of opicapone to human serum proteins is considered, the 1.55 µg/mL Cmax in humans receiving 50 mg/day of opicapone equates to 0.002 µg/mL of unbound material. This is 225-fold lower than the lowest IC50 against transporters (OATP1B1, OATP1B3) and metabolic enzymes (CYP2C8 and CYP2C9) measured in the present study.
Conclusions: Although opicapone inhibited select CYPs and transporters in vitro, because of its high protein binding, the observed in vitro effect upon these biological targets is highly unlikely to have any clinical impact. Nonetheless, caution is advised when co-administering CYP2C8, CYP2C9 or OATP1B1 substrates.
