Pharmacokinetics and Cardiovascular Effects of YM-21095, a Novel Renin Inhibitor,in Dogs and Monkeys |
| |
Authors: | Masayuki Shibasaki Takashi Usui Osamu Inagaki Masaharu Asano Toichi Takenaka |
| |
Abstract: | 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. |
| |
Keywords: | |
|
|