Oxidative metabolism of flunarizine in rat liver microsomes

S. Kariya, S. Isozaki, S. Narimatsu, T. Suzuki

Research output: Contribution to journalArticle

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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 (Cl(f)s) 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 Cl(f)s 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.

Original languageEnglish
Pages (from-to)85-96
Number of pages12
JournalResearch Communications in Chemical Pathology and Pharmacology
Volume78
Issue number1
Publication statusPublished - 1992
Externally publishedYes

Fingerprint

Flunarizine
Liver Microsomes
Metabolites
Metabolism
Liver
Rats
Cinnarizine
Hydroxylation
Cytochrome P-450 Enzyme System
Wistar Rats
Proadifen
Kinetics
Fluorine
Carbon Monoxide
Sex Characteristics
Pharmaceutical Preparations
Isoenzymes
Atoms
Oxidation
Dasyproctidae

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Oxidative metabolism of flunarizine in rat liver microsomes. / Kariya, S.; Isozaki, S.; Narimatsu, S.; Suzuki, T.

In: Research Communications in Chemical Pathology and Pharmacology, Vol. 78, No. 1, 1992, p. 85-96.

Research output: Contribution to journalArticle

Kariya, S, Isozaki, S, Narimatsu, S & Suzuki, T 1992, 'Oxidative metabolism of flunarizine in rat liver microsomes', Research Communications in Chemical Pathology and Pharmacology, vol. 78, no. 1, pp. 85-96.
Kariya, S. ; Isozaki, S. ; Narimatsu, S. ; Suzuki, T. / Oxidative metabolism of flunarizine in rat liver microsomes. In: Research Communications in Chemical Pathology and Pharmacology. 1992 ; Vol. 78, No. 1. pp. 85-96.
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