TY - JOUR
T1 - Oxidative metabolism of cinnarizine in rat liver microsomes
AU - Kariya, Satoru
AU - Isozaki, Sadao
AU - Narimatsu, Shizuo
AU - Suzuki, Tokuji
PY - 1992/10/6
Y1 - 1992/10/6
N2 - The oxidative metabolism of cinnarizine (CZ) [1-(diphenylmethyl)-4-(3-phenyl-2-propenyl)-piperazine] to 1-(diphenylmethyl)piperazine (M-1), 1-(diphenylmethyl)-4-[3-(4′-hydroxyphenyl)-2-propenyl]piperazine (M-2), benzophenone (M-3) and 1-[(4′-hydroxyphenyl)-phenylmethyl]-4-(3-phenyl-2-propenyl)piperazine (M-4) has been studied in rat liver microsomes. In Wistar rats, kinetic analysis revealed sex differences (male > female) in the Km values for formation of all the metabolites and the Vmax values for the formation of M-1, M-3 and M-4. The reactions required NADPH, and were inhibited by carbon monoxide and SKF 525-A. Only M-2 formation was suppressed by sparteine or metoprolol, and was significantly lower in female Dark Agouti rats than in Wistar rats of both sexes. The results suggest that CZ is oxidized by cytochrome P450, and M-2 formation is related to debrisoquine/sparteinetype polymorphic drug oxidation.
AB - The oxidative metabolism of cinnarizine (CZ) [1-(diphenylmethyl)-4-(3-phenyl-2-propenyl)-piperazine] to 1-(diphenylmethyl)piperazine (M-1), 1-(diphenylmethyl)-4-[3-(4′-hydroxyphenyl)-2-propenyl]piperazine (M-2), benzophenone (M-3) and 1-[(4′-hydroxyphenyl)-phenylmethyl]-4-(3-phenyl-2-propenyl)piperazine (M-4) has been studied in rat liver microsomes. In Wistar rats, kinetic analysis revealed sex differences (male > female) in the Km values for formation of all the metabolites and the Vmax values for the formation of M-1, M-3 and M-4. The reactions required NADPH, and were inhibited by carbon monoxide and SKF 525-A. Only M-2 formation was suppressed by sparteine or metoprolol, and was significantly lower in female Dark Agouti rats than in Wistar rats of both sexes. The results suggest that CZ is oxidized by cytochrome P450, and M-2 formation is related to debrisoquine/sparteinetype polymorphic drug oxidation.
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U2 - 10.1016/0006-2952(92)90552-T
DO - 10.1016/0006-2952(92)90552-T
M3 - Article
C2 - 1417969
AN - SCOPUS:0026785612
SN - 0006-2952
VL - 44
SP - 1471
EP - 1474
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 7
ER -