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 language | English |
|---|---|
| Pages (from-to) | 85-96 |
| Number of pages | 12 |
| Journal | Research Communications in Chemical Pathology and Pharmacology |
| Volume | 78 |
| Issue number | 1 |
| Publication status | Published - 1992 |
| Externally published | Yes |
ASJC Scopus subject areas
- Pathology and Forensic Medicine
- Toxicology
- Pharmacology
- Pharmacology, Toxicology and Pharmaceutics(all)