Serum concentrations and urinary excretion of pinacidil and its major metabolite, pinacidil pyridine‐N‐oxide following i.v. and oral administration in healthy volunteers.

Serum concentrations of pinacidil and its major metabolite pinacidil pyridine‐N‐oxide were determined following administration of both an intravenous solution and a sustained release oral preparation to healthy volunteers. Mean bioavailability of pinacidil was 57.1 +/‐ 13.7%. Following intravenous administration, the mean AUC0‐8 h metabolite/AUC 0‐8 h pinacidil ratio was 0.559 +/‐ 0.272 and after oral administration, 0.825 +/‐ 0.656. Only one subject had serum metabolite concentrations in excess of pinacidil during the intravenous study whereas three subjects achieved metabolite concentrations in excess of pinacidil during the oral study. The mean serum elimination half‐life of metabolite was significantly longer than parent drug following intravenous administration (P less than 0.01) but not after oral administration. No significant difference was found in the maximum measured metabolite concentration (Cmax.m) between the studies. The time to Cmax.m was significantly delayed (P less than 0.001) following oral dosage. Twenty four hour urinary excretion of metabolite was significantly increased (P less than 0.001) following oral administration whilst that of pinacidil was decreased (P less than 0.02). These results suggest that pinacidil pyridine‐N‐oxide may be a ‘first‐pass’ metabolite of pinacidil. In most patients pinacidil pyridine‐N‐oxide is unlikely to contribute significantly to the hypotensive effect of pinacidil.