Pharmacokinetics of the new pyrimidine derivative NS-7, a novel Na+/Ca2+ channel blocker. 1st communication: plasma concentrations and excretions after a single intravenous 14C-NS-7 injection to rats, dogs and monkeys.

Abstract

Plasma concentration profiles and excretion were investigated after a single intravenous injection of 14C-NS-7 (4-(fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy)pyrimidine hydrochloride, CAS 178429-67-9), a novel Na+/Ca2+ channel blocker, to rats, dogs and monkeys. Plasma protein binding of this drug was determined in vitro and in vivo. AUC0-infinity values for radioactivity and NS-7 after the intravenous administration of 14C-NS-7 to male rats increased with the dose, namely from 0.04 to 5 mg/kg (radioactivity) and from 0.2 to 5 mg/kg (NS-7), indicating the linearity of the drug's pharmacokinetics. Plasma concentrations of the unchanged drug after the intravenous injection of 0.2 mg/kg 14C-NS-7 decreased biexponentially, respective t1/2 beta values being 15.9 h in the male and 22.4 h in the female rats. The t1/2 beta values difference in the males and females might be due to sex differences in NS-7 metabolism. Urinary and fecal excretions of radioactivity within 168 h of administration were 33.0 and 61.4% of the dose in the male and 35.0 and 53.2% in the female rats. No radioactivity was detected in air exhaled from the males and females collected for 168 h after NS-7 administration. Within 24 h of administration, respective biliary excretions for the male and female rats were 26.1 and 11.9% of the dose. Of this excreted radioactivity, 34.9% was reabsorbed in the males. NS-7 plasma concentrations decreased biexponentially after intravenous administration of 0.2 mg/kg 14C-NS-7 to dogs and monkeys. The elimination half-life was 18 h for the dogs and 9.52 h for the monkeys. Urinary and fecal excretions of radioactivity within 168 h of administration were 24.2 and 70.0% of the dose for the dogs, and 63.3 and 24.8% for the monkeys. These species differences in excretion may be due to differences in urinary metabolite compositions. In vitro protein binding of NS-7 showed no marked species differences and was independent of the NS-7 concentration. Binding of 14C-NS-7 in the sera of rats, dogs, monkeys and humans was 90.7%, 73.5% 79.0% and 87.1%, respectively. Binding to human serum albumin, alpha 1-acid glycoprotein and lipoprotein was 56.2%, 45.4% and 79.5%, in the range of 4-40 ng/ml. In vivo binding in rat serum 5 min, 6 h and 24 h after the intravenous injection of 14C-NS-7(0.2 mg/kg) ranged from 89.6 to 90.6%.