Pharmacokinetics of mefruside and two active metabolites in man

Summary Single oral doses of mefruside 25 or 50 mg were administered to eight healthy human subjects and plasma, red blood cells and urine were assayed for up to 50 h. In four of the subjects, the concentrations of two active metabolites of mefruside, 5-oxomefruside (mefruside-lactone) and its hydroxy carboxylic acid analogue, were also measured. Mefruside was rapidly absorbed into plasma, with a mean half-life of 0.5 h. A 4-fold interindividual difference in elimination half-life was observed, ranging from 2.9–12.5 h. The decay was biphasic in five of the eight subjects. In the other three, who had the shortest t_1/2 values, initial distribution was not visible as a separate phase, so monophasic decay resulted. The variation in t_1/2 was reflected in large differences in total plasma clearance between subjects (22.5–129 l/h). The total volume of distribution ranged from 314–518 l. Mefruside distributed instantaneously between plasma and red cells. The concentration in red cells was about 30 times higher than in plasma, and the terminal decay was parallel to that in plasma. The urinary excretion rate of mefruside also paralleled the plasma concentration curve. A mean total of 0.49% (±0.30%, SD) of the dose was excreted as the unchanged compound in urine over infinite time. Measurable concentrations of 5-oxomefruside were observed in the red cell fraction in the first samples, i. e., at 0.5 h. The carboxylic acid metabolite reached red blood cell concentrations about 10 times lower than those of 5-oxo-mefruside. The plasma concentrations of these metabolites were too low to be measured, but high concentrations were found in urine. Total urinary excretion of the lactone metabolite over infinite time ranged from 12.0–14.5% of dose (mean ± SD, 13.1±1.1%), and that of the open acid metabolite was 34.6–54.2% of dose (mean ± SD, 46.2±9.6%). A further 5–15% of the dose was recovered from urine after enzymatic hydrolysis as a conjugate of the open acid metabolite. The urinary excretion rate of the two main metabolites became maximal between 5–10 h after administration of mefruside, and the subsequent decrease showed much less intersubject variation in t_1/2 than that observed for the parent compound. A mean t_1/2 of 11.9 (±1.7 h, SD) was measured for the lactone, and a mean t_1/2 of 10.5 h (±1.6 h, SD) for the acid metabolite. Approximately the same t_1/2 resulted from red cell measurements. It was concluded that the urinary excretion profile of both metabolites corresponded very well to the known duration of clinical action of mefruside, so that the metabolites instead of the parent drug must be considered as the actual therapeutic principle in man.