title: Oxidative metabolism of flunarizine in rat liver microsomes.
abstract: The oxidative metabolism of flunarizine [1-[bis(4-fluorophenyl)-methyl]-4-(3-phenyl-2-propenyl)piperazine, FZ] to 1-[bis-(4-fluorophenyl)methyl]piperazine (M-1), 1-[bis(4-fluorophenyl)methyl]-4-[3-(4'-hydroxyphenyl)-2- propenyl]piperazine (M-2) and 4,4'-difluorobenzophenone (M-3) has been studied in liver microsomes of Wistar and Dark Agouti (DA) rats. Kinetic analysis demonstrated a sex difference (male > female) in the formation of M-1 and M-3, but not in that of M-2 in Wistar rats. Comparison of the kinetic data of FZ with those of cinnarizine [1-(diphenylmethyl)-4-(3-phenyl-2-propenyl)piperazine, CZ], a prototypic and unfluorinated drug (Kariya et al., Biochem. Pharmacol., in press) revealed that the formation clearances (Clfs) estimated by Vmax/km for the ring hydroxylated metabolites of FZ and CZ are higher than those for the N-dealkylated metabolites of these drugs in female rats. Furthermore, the introduction of two fluorine atoms to CZ (forming FZ) decreased the Clfs for most of metabolites, especially for the N-dealkylated product, M-3. The formation of the metabolites from FZ was suppressed by carbon monoxide and SKF 525-A, and only the ring hydroxylation forming M-2 was significantly lower in female DA than in female Wistar rats. These results suggest that the microsomal oxidation of FZ is mediated by cytochrome P450, and that a cytochrome P450 isozyme(s) belonging to the CYP2D subfamily is involved in the ring hydroxylation of FZ forming M-2.
authors.affiliation: Department of Pharmaceutical Services, Tokyo Teishin Hospital, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kariya
authors.forename: S
authors.initials: S
authors.lastname: Isozaki
authors.forename: S
authors.initials: S
authors.lastname: Narimatsu
authors.forename: T
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D001577:Benzophenones / Q000032:analysis; D002851:Chromatography, High Pressure Liquid; D002936:Cinnarizine / Q000493:pharmacokinetics; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D005444:Flunarizine / Q000031:analogs & derivatives / Q000032:analysis / Q000493:pharmacokinetics*; D005464:Fluorobenzenes / Q000032:analysis; D006900:Hydroxylation; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D010084:Oxidation-Reduction; D010879:Piperazines / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D012737:Sex Factors; D013329:Structure-Activity Relationship
chemical_list: D001577:Benzophenones; D005464:Fluorobenzenes; D010879:Piperazines; C078617:1-(bis(4-fluorophenyl)methyl)-4-(3-(4'-hydroxyphenyl)-2-propenyl)piperazine; C078615:1-(bis(4-fluorophenyl)methyl)piperazine; D002936:Cinnarizine; C078616:4,4'-difluorobenzophenone; D003577:Cytochrome P-450 Enzyme System; D005444:Flunarizine