In vitro characterization of clobazam metabolism by recombinant cytochrome P450 enzymes: importance of CYP2C19.
Article Details
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Giraud C, Tran A, Rey E, Vincent J, Treluyer JM, Pons G
In vitro characterization of clobazam metabolism by recombinant cytochrome P450 enzymes: importance of CYP2C19.
Drug Metab Dispos. 2004 Nov;32(11):1279-86.
- PubMed ID
- 15483195 [ View in PubMed]
- Abstract
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 Km = 29.0, 31.9, and 289 microM, Vmax = 6.20, 1.15, and 5.70 nmol/min/nmol P450, and intrinsic clearance (CLint) = 214, 36.1, and 19.7 microl/min/nmol P450, respectively. NCLB was hydroxylated to 4'-hydroxydesmethylclobazam by CYP2C19 with Km = 5.74 microM, Vmax = 0.219 nmol/min/nmol P450, and CLint = 38.2 microl/min/nmol P450 (Hill coefficient = 1.54). These findings were supported by chemical inhibition studies in human liver microsomes. Indeed, ketoconazole (1 microM) inhibited the demethylation of CLB by 70% and omeprazole (10 microM) 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.
DrugBank Data that Cites this Article
- Drugs
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Clobazam Cytochrome P450 1A2 Protein Humans NoSubstrateDetails Clobazam Cytochrome P450 2B6 Protein Humans NoSubstrateDetails Clobazam Cytochrome P450 2C18 Protein Humans NoSubstrateDetails Clobazam Cytochrome P450 2C19 Protein Humans NoSubstrateDetails Clobazam Cytochrome P450 2C8 Protein Humans NoSubstrateDetails Clobazam Cytochrome P450 3A4 Protein Humans NoSubstrateInducerDetails Clobazam Cytochrome P450 3A5 Protein Humans NoSubstrateDetails Clobazam Cytochrome P450 3A7 Protein Humans NoSubstrateDetails - Drug Reactions
Reaction Details Details - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareClobazamChloramphenicol The serum concentration of Clobazam can be increased when it is combined with Chloramphenicol. ClobazamLansoprazole The serum concentration of Clobazam can be increased when it is combined with Lansoprazole. ClobazamZafirlukast The serum concentration of Clobazam can be increased when it is combined with Zafirlukast. ClobazamIsoniazid The serum concentration of Clobazam can be increased when it is combined with Isoniazid. ClobazamMiconazole The serum concentration of Clobazam can be increased when it is combined with Miconazole. - Pharmaco-genomics
Drug Interacting Gene/Enzyme Allele name Genotypes Defining change(s) Type(s) Description Details Clobazam Cytochrome P450 2C19
Gene symbol: CYP2C19
UniProt: P33261CYP2C19*2 (A;A) / (A;G) - G > A/C (rs4244285)
ADR Directly Studied Patients with this genotype have reduced metabolism of clobazam. Details
