title: Lack of CYP3A4 inhibition by grapefruit juice and ketoconazole upon clozapine administration in vivo.
abstract: The drug-food and drug-drug interaction between grapefruit juice (GFJ) and ketoconazole (KETO) was evaluated in schizophrenic patients given a single dose of clozapine (CLZ). CLZ is metabolized primarily by CYP isozymes 3A4 and 1A2 to two principal metabolites, desmethylclozapine (DCLZ) and clozapine N-oxide (CNO). GFJ and KETO are well known potent CYP 3A4 inhibitors in the gastrointestinal tract and hepatic isozymes, respectively. Twenty-one schizophrenic patients participated in the co-administration of CLZ 50 mg and GFJ. After a one-week washout, five patients were given double the GFJ (HGFJ) dose for 7 consecutive days. In another group of five patients, ketoconazole (KETO) 400 mg was given for 7 consecutive days. At the end of the 7-day period for both groups, CLZ was coadministered with the HGFJ and KETO groups. CLZ, DCLZ and CNO were assayed by HPLC. GFJ, HGJF and ketoconazole failed to significantly change CLZ disposition. Metabolites DCLZ and CNO concentrations remained unchanged during the study. The only exception was decreased Cmax in DCLZ and CNO concentrations. These results indicate that CYP 3A4 inhibition may not be clinically significant compared to CYP 1A2, as previous studies show a dramatic increase in CLZ plasma concentrations with fluvoxamine (CYP 1A2 inhibitor). The reasons for the lack of drug-food and drug-drug interactions with CLZ and CYP 3A4 inhibitors can be explained by the higher Ki values for gastrointestinal and hepatic CYP 3A4 isozymes.
authors.affiliation: Department of Psychiatry, Tzi-Chi General Hospital and Tzu Chi University School of Medicine, Hualien City, Taiwan.
authors.forename: H Y
authors.initials: HY
authors.lastname: Lane
authors.forename: C C
authors.initials: CC
authors.lastname: Chiu
authors.forename: Y
authors.initials: Y
authors.lastname: Kazmi
authors.forename: H
authors.initials: H
authors.lastname: Desai
authors.forename: Y W
authors.initials: YW
authors.lastname: Lam
authors.forename: M W
authors.initials: MW
authors.lastname: Jann
authors.forename: W H
authors.initials: WH
authors.lastname: Chang
mesh_terms: D000328:Adult; D000935:Antifungal Agents / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000097:blood* / Q000627:therapeutic use; D001628:Beverages; D002957:Citrus; D003024:Clozapine / Q000097:blood* / Q000627:therapeutic use; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018565:Food-Drug Interactions; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000502:physiology; D012559:Schizophrenia / Q000097:blood* / Q000188:drug therapy
chemical_list: D000935:Antifungal Agents; D014150:Antipsychotic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D003024:Clozapine; D007654:Ketoconazole