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Oxidative metabolism of flunarizine in rat liver microsomes
S Kariya1, S Isozaki, S Narimatsu
1Department of Pharmaceutical Services, Tokyo Teishin Hospital, Japan.
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.
Insights
Flunarizine metabolism in rats shows sex differences and is influenced by fluorine atoms. Cytochrome P450 enzymes, particularly CYP2D, are involved in flunarizine
Area of Science:
- Pharmacology
- Drug Metabolism
- Toxicology
Background:
- Flunarizine (FZ) is a drug with a known metabolic pathway.
- Understanding FZ metabolism is crucial for its safe and effective use.
- Cytochrome P450 enzymes play a significant role in drug metabolism.
Purpose of the Study:
- To investigate the oxidative metabolism of flunarizine (FZ) in rat liver microsomes.
- To compare the metabolic pathways of FZ with cinnarizine (CZ).
- To identify the specific cytochrome P450 isozymes involved in FZ metabolism.
Main Methods:
- Incubation of FZ with liver microsomes from Wistar and Dark Agouti (DA) rats.
- Kinetic analysis of metabolite formation (M-1, M-2, M-3).
- Enzyme inhibition studies using carbon monoxide and SKF 525-A.
Main Results:
- Sex differences (male > female) observed in M-1 and M-3 formation in Wistar rats.
- Fluorine substitution in CZ to form FZ decreased metabolite formation clearances (Clfs).
- CYP2D subfamily likely involved in ring hydroxylation of FZ to form M-2.
Conclusions:
- Microsomal oxidation of FZ is mediated by cytochrome P450 enzymes.
- CYP2D isozyme(s) are implicated in the ring hydroxylation of FZ.
- Metabolism of FZ exhibits sex-specific differences and is affected by its chemical structure.