DISPOSITION OF THE NEW ANTIRHEUMATIC AGENT ETHYL -(1,2,4-TRIAZOL-1-YLMETHYL)QUINOLINE-3-CARBOXYLATE (TAK-603) IN RATS AND DOGS

The disposition of ethyl phenyl)-6,7-dimethoxy-2-(1,2,4-triazol-1-ylme thyl) quinoline-3-carboxylate (CAS 158146-85-1, TAK-603) after single oral dosing of C-14-labeled TAK-603 ([C-14]TAK-603) at 10 mg/kg to rat s and dogs was studied. In rats, the concentration of unchanged drug i n plasma reached a peak (C-max 0.31 mu g/ml) 2 h (T-max) after dosing of TAK-603 and declined biphasically with apparent half-lives (t(1/2)a lpha, t(1/2)beta) of 1.5 and 3.6 h. In dogs. T-max, C-max, t(1/2)alpha , and t(1/2)beta were 1.7 h, 0.36 mu g/ml, 1.2, and 10.8 h, respective ly. [C-14]TAK-603 dosed orally was absorbed quantitatively in rats, wh ile the extent of absorption in dogs was 54 %. The bioavailability of TAK-603 was 53 % and 42 % in rats and dogs, respectively. In rats, C-1 4 waS distributed widely in various tissues, with relatively high conc entrations in the liver, adrenal gland, and gut. The elimination of C- 14 from the thyroid was slower than that from other tissues. Unchanged TAK-603 and its pharmacologically active metabolite, M-I, which has t he same potency as TAK-603, were distributed in articular soft tissues and synovial fluids, as target tissues, in rats and dogs, respectivel y. After oral administration of [C-14]TAK-603, most of the C-14 dosed was excreted within 48 h in rats and within 96 h in dogs. In both anim als, a greater amount of the C-14 dosed was excreted in feces than in urine. In biliary duct cannulated rats given [C-14]TAK-603 intraduoden ally, 69 % of the dose was excreted in bile, and biliary C-14 in part underwent enterohepatic circulation.