Oxidative metabolism of cinnarizine in rat liver microsomes.
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/sparteine-type polymorphic drug oxidation.
Kariya
S
S
Department of Pharmaceutical Services, Tokyo Teishin Hospital, Japan.
Isozaki
S
S
Narimatsu
S
S
Suzuki
T
T
D000818:Animals; D002936:Cinnarizine / Q000737:chemistry / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000172:deficiency; D005260:Female; D007700:Kinetics; D008297:Male; D008790:Metoprolol / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000172:deficiency; D008956:Models, Chemical; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar; D013034:Sparteine / Q000494:pharmacology
D065607:Cytochrome P-450 Enzyme Inhibitors; D013034:Sparteine; D002936:Cinnarizine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; D008790:Metoprolol