Pharmacokinetics and safety of a novel, long-acting, prodrug-type potassium channel opener, Y-27152, in healthy volunteers.

The pharmacokinetics and safety of a novel, long-acting, prodrug-type K(+)-channel opener, Y-27152, were investigated in healthy male volunteers. In the first phase, single oral doses of 0.1, 0.25, 0.5, 0.75, and 1.0 mg of Y-27152 (n = 3-6 per dose) were given after overnight fasts in a dose-escalating manner. The 0.75-mg dose was given both after an overnight fast or after food to examine the effects of food intake. In the second phase, multiple doses of Y-27152 were taken after meals once daily for 7 consecutive days. In part A of this phase, either placebo (n = 3) or 0.5 mg of Y-27152 (n = 6) was taken for 7 days, and in part B of this phase 0.5-, 0.75-, and 1.0-mg doses were taken in a dose-escalating manner for 1,3, and 3 days, respectively (n = 9). In the single-dose study, peak concentration (Cmax) and area under the plasma concentration-time curve (AUC) of main active metabolite (Y-26763; M1) increased in parallel with dosage. This dose-linearity was less obvious with Y-27152, which had an AUC approximately 6 to 10 times less than that of M1. Administration with food at 0.75 mg resulted in a small but significant decrease (approximately 10%) in the Cmax and AUC of M1. At doses of 0.5 mg or higher, participants experienced headaches and palpitations, which were probably due to the vasodilatory effects and did not require treatment. Mean diastolic blood pressure significantly decreased and pulse rate increased at doses of 0.5 mg or higher compared with predose values. Plasma renin activity was significantly elevated 4 hours after the administration of the 0.75- and 1.0-mg doses, but showed no significant change at 0.5 mg. In the multiple-dose study, the time profile of the plasma concentration of M1 approximately coincided with the simulation curves worked out using the pharmacokinetic parameters obtained in the singledose study. The incidence of headaches tended to increase with dose in part B, but drug administration was not discontinued in any case. Plasma renin activity again increased 4 hours after administration. In phase B of the multiple-dose study, diastolic blood pressure decreased and pulse rate increased compared with predose values. Y-27152 was metabolized to M1 and well tolerated in healthy volunteers, and its pharmacologic effects were likely caused by vasodilation, which could make it an effective antihypertensive agent.