In vitro metabolism of bencycloquidium bromide and its inhibitory effects on human P450 isoenzymes: implication of CYP2D6, CYP2C19 and CYP3A4/5

Abstract

Bencycloquidium bromide (BCQB) is a novel selective muscarinic M1/M3 receptor antagonist with potent therapeutic effects on rhinitis and chronic obstructive pulmonary disease. The metabolism of BCQB has been investigated in human liver microsomes and human recombinant P450 to elucidate the P450 isozymes responsible for its metabolism in human. Also, the metabolism pathway and the potency of BCQB in inhibiting CYP’s various isozymes in humans were investigated. The main biotransformation route of BCQB was NADPH-dependent oxidation. BCQB was metabolized oxidatively to four metabolites that were identified as monohydroxylated derivatives of BCQB at the phenyl and pentyl moieties of the molecule. The results from in vitro inhibition studies indicated that quinidine inhibited 86 % of metabolism of BCQB, while ticlopidine and ketoconazole inhibited 39 and 29 %, respectively. Inhibition studies with selective chemical inhibitors and incubations with human recombinant P450 isoforms demonstrated that the oxidative metabolism of BCQB is mediated by CYP2D6, CYP2C19 and CYP3A4/5, whereas BCQB had no inhibitory effect on any other P450 isoenzyme in humans.