Pharmacokinetics and hypotensive effect in healthy volunteers of pinacidil, a new potent vasodilator

Preliminary investigation in 3 healthy volunteers suggested that intravenous pinacidil in a dose of 0.2 mg/kg had a potent but well-tolerated hypotensive action in the supine position. Facial flushing, uncomfortable chest sensation and distressing postural hypotension occurred at serum concentrations above 300 ng/ml. Pinacidil, 0.2 mg/kg, was given intravenously over 4 min to 15 healthy volunteers in the supine position. Maximum fall in mean arterial pressure (MAP) was 15.7±6.0 mmHg. Maximum rise in heart rate was 23.8±6.6 beats/min. Pinacidil serum distribution half-life ( \({\text{T}}_{{\raise0.7ex\hbox{\({\text{1}}\)} \!\mathord{\left/ {\vphantom {{\text{1}} {{\text{2}}\alpha }}}\right.\kern-0em}\!\lower0.7ex\hbox{\({{\text{2}}\alpha }\)}}}\) ) was 13.4±8.5 min and elimination half-life ( \({\text{T}}_{{\raise0.7ex\hbox{\({\text{1}}\)} \!\mathord{\left/ {\vphantom {{\text{1}} {{\text{2}}\beta }}}\right.\kern-0em}\!\lower0.7ex\hbox{\({{\text{2}}\beta }\)}}}\) ) was 2.13±0.49 h. The apparent volume of distribution (Vd_β) was 90.3±13.21 and total body clearance was 31.1±9.61/h. Pinacidil was approximately 40% bound to plasma protein over the concentration range 40–400 ng/ml. Urinary excretion of unchanged pinacidil accounted for 5.7 ± 1.3% of the administered dose over 24 hours and urinary excretion of the major metabolite, pinacidil pyridine-N-oxide, was 31.6±9.2% of the administered dose. It was concluded that intravenous pinacidil is a potent vasodilator hypotensive compound, with a duration of action between 1.5 and 2 h.