Abstract

5-(2'4'-Difluorophenyl)[carboxy-¹⁴C]salicyclic acid (MK-647) was quickly and completely absorbed in rats, dogs, and man. Peak levels of plasma radioactivity occurred in 1-2 hr after oral administration. The dose was 10 mg/kg in rats and dogs, and 50 or 500 mg in man. Most of the drug in plasma was intact MK-647 which was extensively bound to plasma protein. In man the peak concentration following the 500-mg dose was approximately 10 times that after the lower dose, which suggests that absorption rates of both doses were similar. Elimination of drug from plasma was dose-dependent. The area under the curve for MK-647-¹⁴C in plasma was 18 times higher following the 500-mg dose than the 50-mg dose. Dogs given 10 mg/kg orally or intravenously excreted 44% of the dose in the urine and 42% in the feces in 72 hr. Rats given the same dose level by either route of administration excreted 80% in the urine and 11% in the feces. In man, approximately 95% of a 50- or 500-mg oral dose was excreted in the urine and 3% in the feces, in 96 hr. MK-647 and two metabolites were present in the urine of the three species. The ether and ester glucuronides were identified in human urine. The latter metabolite was also identified in rat and dog urine. The glycine conjugate of MK-647 was not observed in the urine of the three species. No interaction was observed between MK-647 and bishydroxycoumarin in the prothrombin time test nor with tolbutamide in the glucose tolerance test. A significant lowering of hexobarbital sleeping time was observed in female, but not male rats after four consecutive daily doses of MK-647. After repeated daily administration of MK-647 (12.5-100 mg/kg), the diurnal plasma level in dogs was not significantly altered, indicating that no saturation, induction, or inhibition of its own metabolism took place.