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IN VITRO CHARACTERIZATION OF CLOBAZAM METABOLISM BY RECOMBINANT CYTOCHROME P450 ENZYMES: IMPORTANCE OF CYP2C19

Pharmacologie, Groupe Hospitalier Cochin-Saint-Vincent de Paul, Assistance Publique-Hôpitaux de Paris, Université René Descartes (C.G., E.R., J.M.T., G.P.); Ecole Pratique des Hautes Etudes (A.T.), Paris; and Laboratoires Biocodex, Montrouge (J.Y.), France

The specific cytochrome P450 (P450) isoforms mediating the biotransformations of clobazam (CLB) and those of its major metabolites, N-desmethylclobazam (NCLB) and 4'-hydroxyclobazam were identified using cDNA-expressed P450 and P450-specific chemical inhibitors. Among the 13 cDNA-expressed P450 isoforms tested, CLB was mainly demethylated by CYP3A4, CYP2C19, and CYP2B6 and 4'-hydroxylated by CYP2C19 and CYP2C18. CYP2C19 and CYP2C18 catalyzed the 4'-hydroxylation of NCLB. The kinetics of the major biotransformations were studied: CYP3A4, CYP2C19, and CYP2B6 mediated the formation of NCLB with K_m = 29.0, 31.9, and 289 µM, V_max = 6.20, 1.15, and 5.70 nmol/min/nmol P450, and intrinsic clearance (CL_int) = 214, 36.1, and 19.7 µl/min/nmol P450, respectively. NCLB was hydroxylated to 4'-hydroxydesmethylclobazam by CYP2C19 with K_m = 5.74 µM, V_max = 0.219 nmol/min/nmol P450, and CL_int = 38.2 µl/min/nmol P450 (Hill coefficient = 1.54). These findings were supported by chemical inhibition studies in human liver microsomes. Indeed, ketoconazole (1 µM) inhibited the demethylation of CLB by 70% and omeprazole (10 µM) by 19%; omeprazole inhibited the hydroxylation of NCLB by 26%. Twenty-two epileptic patients treated with CLB were genotyped for CYP2C19. The NCLB/CLB plasma metabolic ratio was significantly higher in the subjects carrying one CYP2C19^*2 mutated allele than in those carrying the wild-type genotype. CYP3A4 and CYP2C19 are the main P450s involved in clobazam metabolism. Interactions with other drugs metabolized by these P450s can occur; moreover, the CYP2C19 genetic polymorphism could be responsible for interindividual variations of plasma concentrations of N-desmethylclobazam and thus for occurrence of adverse events.

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