Isomazole disposition in man as a function of dose and route of administration.

The disposition of a new cardiotonic agent (isomazole (ISO] was evaluated in healthy volunteers after various single oral (p.o.), intravenous (i.v.), and multiple p.o. doses. Blood samples were collected after dosing in all studies, with urine collected in the single i.v. and multiple dose studies. All biological samples were measured for ISO. In the multiple dose study, samples were collected for analysis after the first and last doses administered. In addition to ISO, several known metabolites (hydroxyisomazole (OHISO), sulfone (SULF), and hydroxysulfone (OHSULF) analogs) were measured after the first and last doses given in the multiple dose study. Pharmacokinetic values compared between doses suggested no saturable processes existed over the entire dose range. The single i.v. dose data showed ISO experienced some extravascular distribution (mean V beta = 1.82 l kg-1), with a high clearance (mean Cls = 18.8 ml min-1 kg-1) and a short half-life (mean t 1/2 = 1.1 h). Elimination was primarily nonrenal (Clr = 3.5 ml min-1 kg-1). Single p.o. data supported these findings and further suggested rapid absorption. ISO data from the first dose of the multiple dose study was in agreement with these data; however, the last dose showed a higher Cls (33.0 ml min-1 kg-1) (p = 0.055). Although not statistically significant, metabolite plasma data and and urinary excretion patterns changed. An increase was observed in plasma AUC and metabolite excretion of SULF and OHSULF, while a decrease was observed in the same parameters for OHISO. These results suggest that multiple dosing of ISO produces autoinduction of ISO metabolism through selective metabolic routes.