PHARMACOKINETICS AND METABOLISM OF THE NEW THROMBOXANE A(2) RECEPTOR ANTAGONIST RAMATROBAN IN ANIMALS - 1ST COMMUNICATION - ABSORPTION, CONCENTRATIONS IN PLASMA, METABOLISM, AND EXCRETION AFTER SINGLE ADMINISTRATION TO RATS AND DOGS

The absorption, concentrations in plasma, metabolism and excretion of ramatroban lfonamido)-1,2,3,4-tetrahydro-9-carbazolepropanoic acid, CA S 116649-85-5, BAY u 3405) have been studied following a single intrav enous, oral, or intraduodenal administration of C-14-labeled or non-la beled compound to rats and dogs (dose range: 1-10 mg.kg(-1)). After in traduodenal administration of [C-14]ramatroban, enteral absorption of radioactivity was rapid and almost complete both in bile duct-cannulat ed male rats (83%) and female dogs (95%). The oral bioavailability of ramatroban was complete in the dog but amounted to about 50% in the ra t due to presystemic elimination. A marked food effect on the rate but not on the extent of absorption was observed in rats. The elimination of the parent compound from plasma occurred rapidly with total cleara nce of 1.21.h(-1).kg(-1) in male rats and 0.71.h(-1).kg(-1) in dogs. A fter oral administration to male rats AUC increased dose-proportionall y between 1 and 10 mg.kg(-1), whereas in C-max an over-proportional in crease was observed. Excretion of total radioactivity was fast and occ urred predominantly via the biliary/fecal route in both species. The r esidues were low, 144 h after dosing less than 0.2% of the radioactivi ty remained in the body of rats. A considerable sex difference was fou nd in rats following oral administration of ramatroban. In females a 3 -fold higher AUC and a 1.7-fold longer half-life of unchanged compound , as well as 3-fold higher renal excretion of total radioactivity was observed. A marked species difference exists in the metabolism of rama troban. In dogs the drug was almost exclusively metabolized via conjug ation with glucuronic acid, whereas in rats oxidative phase I metaboli sm and glucuronidation were equally important. As a consequence entero hepatic circulation was much more pronounced in dogs (77%) than in rat s (17% of the initial dose).