HEMODYNAMICS, BIOCHEMICAL EFFECTS, AND PHARMACOKINETICS OF THE RENIN INHIBITOR REMIKIREN IN HEALTHY-HUMAN SUBJECTS

Introduction: Remikiren (Ro 42-5892) is a potent and specific inhibito r of human renin in vitro. Its in vivo action on plasma renin activity (PRA), immunoreactive renin, and blood pressure has been shown in pil ot studies in humans. Objective: To investigate tolerability, hemodyna mic effects, and biochemical effects of remikiren in relation to its p harmacokinetics after single ascending intravenous and oral doses in h ealthy humans. Methods. In this double-blind, placebo-controlled, two- way crossover (intravenous and oral) study, single ascending doses of 10, 20, 40, 80, 160, and 320 mg (intravenous) and 100, 200, 400, 800, and 1600 mg (oral) were given; six subjects received active drug and t hree received placebo at each dose level. At regular intervals, blood pressure, heart rate, cardiac output, PRA, immunoreactive renin, and d rug plasma levels were determined. Results. The compound was well tole rated except at the 1600 mg oral dose level at which diarrhea occurred in two subjects. At neither dose were there effects on blood pressure , heart rate, or cardiac output relative to placebo. PRA and angiotens in I production rate decreased and immunoreactive renin increased dose dependently after both intravenous and oral administration. The durat ion of these effects was also dose dependent and was longer than 12 ho urs with higher doses. Systemic plasma clearance, volume of distributi on, and absolute bioavailability of remikiren were in the magnitude of 900 ml/min, 70 L, and below 1%, respectively. The angiotensin I produ ction rate correlated in a sigmoidal way with plasma drug concentratio ns independent of the route of administration. Conclusion: Remikiren i s a potent inhibitor of renin in humans with long-lasting effects afte r both intravenous and oral administration.