Comparison of the disposition of two novel combined thromboxane synthase inhibitors/thromboxane A2 receptor antagonists in the isolated perfused rat liver.

1. The pharmacokinetics of two combined thromboxane synthase inhibitor/thromboxane A2 receptor antagonists were investigated in an isolated perfused rat liver preparation. 2. The clearance of both UK 101613 (15.4 +/- 1.9 ml/min) and UK 102333 (14.9 +/- 1.6 ml/min) was limited by hepatic bloodflow. Both hepatic uptake and biliary excretion of UK 101613 appeared to be active processes. The apparent biliary clearance of UK 101613 (10.3 +/- 2.3 ml/min) was less than perfusate clearance, indicating accumulation within the hepatocytes. 3. The efficiency of the active hepatic uptake of UK 101613 and UK 102333 explains the rapid removal of these compounds from the systemic circulation. The processes of biliary and/or metabolic clearance of UK 101613 and UK 102333 appear to be subsequent to and independent of perfusate clearance. 4. Although the compounds are of similar structure and have a similar hepatic extraction (> 0.9), UK 101613 had an apparent biliary clearance approximately twice that of UK 102333. This is due to the formation of a metabolite of UK 102333 which reduces the amount of parent compound available for biliary excretion. 5. Inhibition of this latter metabolism by ketoconazole (10 microM) resulted in the two compounds having comparable apparent biliary clearances.