Studies on the Metabolic Fate of Leukotriene Antagonist ONO-1078 (2) : Absorption, Distribution, Excretion and Effects on Drug Metabolizing Enzyme Activities after Repeated Oral Administration to Rats

The absorption, distribution and excretion of ONO-1078(4-oxo-8-[4-(4-phenylbutoxy)benzoylamino]-2-(tetrazol-5-yl)-4H-1-benzopyran hemihydrate) after repeated oral administration were investigated in rats. Also the influence on the hepatic drug metabolizing enzyme activities was examined. 1. When 3H-ONO-1078 was orally and repeatedly administered at the dose of 2mg/kg/day for 15 days, the plasma level of radioactivity at 24hr after each administration reached nearly steady state by 5-7th day. 2. Repeated oral administration of 14C-ONO-1078 at the dose of 2 mg/kg/day for 7 days was not associated with any accumulation of radioactivity in organs or tissues, the radioactivity was quickly eliminated after final administration. 3. When 3H-ONO-1078 was orally and repeatedly administered at the dose of 2mg/kg/day for 7 or 15 days, radioactivity reached nearly steady state in many organs such as liver and kidney. On the other hand, the radioactivity in white and brown fat did not reach steady state by 15-day repeated administration. 4. After repeated oral administration of 14C-ONO-1078 or 3H-ONO-1078 at the dose of 2mg/kg/day, the excretion of radioactivity into urine or feces were same to those after single administration. 5. Repeated oral administration of ONO-1078 at the dose of 1.0g/kg/day for 15 days did not have any effect on microsomal protein content and hepatic drug metabolizing enzyme activities, but liver weight rose 1.08-fold heigher than normal control.