Sex differences in the metabolism and excretion of nilvadipine, a new dihydropyridine calcium antagonist, in rats.
1. The metabolic profiles of nilvadipine in the urine and bile of male and female rats were studied after i.v. dosing with 1 mg/kg of the 14C-labelled compound. 2. Excretion rates of the dosed radioactivity in male and female rats, respectively, in the first 48 h were 84.1% and 59.1% in bile, 12.0% and 36.9% in urine, and 2.5% and 3.6% in faeces. 3. Comparison of biliary and urinary excretion for each radioactive metabolite after dosing with 14C-nilvadipine, showed marked sex-related differences in the excretion routes of several metabolites. In male rats, metabolite M3, having a free 3-carboxyl group on the pyridine ring, was not excreted in urine, but in female rats urinary excretion of M3 accounted for 4.7% of the dose. One reason for the lower urinary excretion of radioactivity by males than by females was that the main metabolite, M3, was not excreted in the urine of the male rats. 4. To clarify the sex difference in the route of excretion of M3, this metabolite (M3) was given i.v. to rats. No excretion of the metabolite was observed in urine of male rats within 24 h but, in marked contrast, 41.5% of the dose was excreted in urine of females in the same period.
Terashita
S
S
Product Development Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Tokuma
Y
Y
Sekiguchi
M
M
Noguchi
H
H
D000818:Animals; D001646:Bile / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D005260:Female; D007275:Injections, Intravenous; D007700:Kinetics; D008297:Male; D009543:Nifedipine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D011919:Rats, Inbred Strains; D012727:Sex Characteristics
D002121:Calcium Channel Blockers; C035100:nilvadipine; D009543:Nifedipine