Abstract:The pharmacokinetics and cardiovascular effects of YM-21095 ((2 RS), (3S)-3-[Nα-[1,4-dioxo-4-morpholino-2-(1-naphthylmethyl)-butyl]-l-histidylamino]-4-cyclohexyl-1-[(1-methyl-5-tetrazolyl)thio]-2-butanol), a potent renin inhibitor, have been studied in beagle dogs and squirrel monkeys. Plasma levels of YM-21095 after 3 mg kg−1 intravenous dosing to dogs declined biphasically and fitted a two-compartment model. Kinetics were as follows: t½α = 4·9±0·2 min, t½β = 2·76±0·79 h, Vdss = 3·86±1·04 L kg−1, plasma clearance = 2·22 ± 0·39 L kg−1, and AUC= 1445 ± 266 ng h mL−1. After 30 mg kg−1 oral dose, maximum plasma concentration, tmax and AUC of YM-21095 were 28·8 ± 9·6 ng mL−1, 0·25 h and 23·6 ± 7·7 ng h mL−1, respectively. Systemic bioavailability as determined on the basis of the ratio of AUC after intravenous and oral dose was 0·16 ± 0·04%. In conscious, sodium-depleted monkeys, YM-21095 at an oral dose of 30 mg kg−1 lowered systolic blood pressure and inhibited plasma renin activity without affecting heart rate and plasma aldosterone concentration. Maximum plasma concentration of YM-21095 after 30 mg kg−1 oral dose to monkeys was 71·8 ± 41·5 ng mL−1, which was reached 0·5 h after the dose. At equihypotensive doses, captopril and nicardipine increased plasma renin activity markedly and slightly, respectively. These results suggest that oral absorption of YM-21095 is low in dogs and monkeys, and YM-21095 shows a blood pressure lowering effect by inhibiting plasma renin activity in sodium-depleted monkeys.