DISPOSITION OF SCH 10595 IN ANIMALS AND MAN

¹ Department of Biochemistry, Schering Corporation, Bloomfield, New Jersey

The absorption, metabolism and excretion of isotopically (¹⁴C) labeled Sch 10595 [5-(n-butyl)-picolinamide] (I) were studied in the rat and compared with observations made in man, dog and monkey. In the rat, peak plasma levels of radioactivity occurred around 2.5 hours after oral administration of ¹⁴C-I (100 mg/kg) with an estimated half-life (T) of 4.2 hours. Thirty minutes after dosing, less than 10% of radioactivity was I. The major metabolite in plasma was chromatographically identical to fusaric acid [5-(n-butyl)-picolinic acid] (II). After 24 hours, 61 and 12% of the administered dose of ¹⁴C was recovered from the urine and feces, respectively. A complex pattern of urinary metabolites was found, containing only relatively small amounts of I and II. In man. 1 hour after an oral dose (15 mg/kg) I could not be detected in the plasma. The major metabolite in the plasma (by thin-layer chromatography) was II, and it reached maximum concentration in about 2 hours with an estimated T of 8.7 hours. The peak plasma level in man (60.4 µg/ml) after a 15 mg/kg dose approximated the levels found after a 75 to 100 mg/kg dose in the rat (70.0 µg/ml), dog (77.6 µg/ml) and monkey (50.8 µg/ml). The area of plasma concentration-time (24 hours) curve in man was equal to or greater than that found for the rat, dog and monkey at the higher dosage levels.