Nonlinear pharmacokinetics of the new positive inotropic agent sulmazole in the dog

Abstract

Sulmazole (I) 2-[2-methoxy-4-(methylsulfinyl)phenyl]-1H-imidazo[ 4,5-b]pyridine, a new positive inotropic agent, is based on a pyridoimidazole nucleus. Sulmazole pharmacokinetics were monitored in plasma and urine by a specific, sensitive reverse-phase fully automated HPLC system with fluorimetric detection. The hydroxylated metabolite, III, was also monitored in the urine, and unusual pharmacokinetics were observed. Sulmazole disappeared and metabolite II appeared in plasma by zero-order rates for most of their time courses in the 2-15-mg/kg range with a 75% conversion to II. Pure Michaelis-Menten pharmacokinetics were not applicable, and the vmax value increased with increasing dose. Pharmacokinetics of sulmazole and II at 0.7-mg/kg iv doses were characterized by a first-order two-compartment body model. Metabolite III at 0.7- and 2-mg/kg iv doses showed no dose-dependent pharmacokinetics. The unchanged drug and its major metabolite, II, were negligibly excreted renally (0.5-2%). Their renal clearance showed urine flow rate dependencies. The plasma protein bindings were: sulmazole, 40.8 +/- 1.0%; II, 54 +/- 2%; III, 43 +/- 1%, and they were concentration independent.