Sex difference in the stereoselective metabolism of a new dihydropyridine calcium channel blocker, in rat studies in vivo and in vitro.
1. After oral dosing with a new racemic dihydropyridine calcium channel blocker (I), plasma levels of (+/-)-I, the 3-desisopropyl metabolite (M-2), the pyridine metabolite (M-3) and the 5-desmethyl metabolite (M-10) in female rats were higher than in males, and plasma levels of (+)-I were higher than those of the (-)-enantiomer in both sexes. 2. Plasma levels of M-2 after oral dosing with (-)-I were much higher than those after dosing with (+)-I, in both male and female rats. 3. Stereoselective metabolism of I by rat liver microsomes was shown in the formation of the 3-(2'-hydroxy-1'-methylethyl) ester metabolite (M-1), and metabolites M-2 and M-10. 4. Marked sex differences were seen in the formation of M-1 and M-3 in adult rats (7 weeks of age), but not in immature rats (3 weeks of age). 5. In liver microsomes of rats pretreated with phenobarbital, the formation of M-1 was decreased in adult male rats, and formation of M-2 and M-3 was increased in adult rats of both sexes.
Takayama
F
F
Central Research Laboratories, Banyu Pharmaceutical Co., Ltd., Tokyo, Japan.
Saito
K
K
Ishii
Y
Y
Shiratori
K
K
Ohtawa
M
M
D000818:Animals; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics*; D004095:Dihydropyridines / Q000493:pharmacokinetics*; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012737:Sex Factors; D013237:Stereoisomerism
D002121:Calcium Channel Blockers; D004095:Dihydropyridines