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POTENTIAL FOR DRUG INTERACTION OF THE NOVEL COMT INHIBITOR OPICAPONE
Author(s) -
Loureiro Ana Isabel,
FernandesLopes Carlos,
SoaresdaSilva Patrício
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.822.13
Subject(s) - pharmacology , drug metabolism , efflux , chemistry , cyp2c8 , in vitro , cytochrome p450 , drug , microsome , abcg2 , organic anion transporting polypeptide , transporter , cyp2c9 , biochemistry , metabolism , biology , atp binding cassette transporter , gene
Objectives The effect of opicapone, a third generation COMT inhibitor, on metabolic enzymes and drug transporters was evaluated in vitro to anticipate potential drug‐drug interactions. Methods in vitro studies using human liver microsomes and cell‐lines overexpressing a panel of selected drug‐transporters. Results When tested against P450 cytochromes (CYP), opicapone was found to be reversible inhibitor of CYP2C8 (IC 50 = 3.6 μg/ml and IC 50 = 6.7 μg/ml, respectively) and CYP2C9 (IC 50 = 9.6 μg/ml, and IC 50 = 20.7 μg/ml, respectively). No metabolism dependent inhibition by opicapone was observed for all tested CYPs. Opicapone was a substrate for the efflux transporters breast cancer resistance protein (BCRP) and P‐glycoprotein (P‐gp) and for the organic anion transporting polypeptide (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 (IC 50 values of 0.45 and 1.4 μg/ml, respectively). Conclusions When the 99.9% binding of opicapone to human serum proteins is considered, the 1.55 μg/mL C max 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 IC 50 against transporters (OATP1B1, OATP1B3) and metabolic enzymes (CYP2C8 and CYP2C9) measured in the present study. As such, the observed in vitro effect upon these biological targets is highly unlikely to have any clinical impact.