FIRST-PASS EFFECT OF N-METHYL-N(2-(1-PYRROLIDINYL)-CYCLOHEXYL)BENZAMIDE (U-54494) IN RATS - A MODEL WITH MULTIPLE CANNULAS FOR INVESTIGATION OF GASTROINTESTINAL AND HEPATIC-METABOLISM

A multiple cannulated rat model was utilized to investigate the relati ve contribution of the gut and liver as sites of first-pass metabolism of orally administered U-54494A, an anticonvulsant drug candidate. Ea ch rat received a dose of U-54494A by oral, intraportal, and intraveno us routes on three separate occasions. Intraportal and intravenous dos es were administered through chronic cannulas surgically implanted in the portal vein and superior vena cava, respectively. Blood samples we re collected over a 6-hr period from the superior vena cava cannula. T he mean (n=3) bioavailability of orally dosed U-54494A was 4.5 +/- 1.1 %, while that dosed intraportally was 19.1 +/- 3.0%. The relative cont ribution of the gut and liver as sites of first-pass extraction and/or metabolism of orally administered drug was 69.9 +/- 14.0% and 24.5 +/ - 12.2%, respectively. Approximately 35 to 40% of the total plasma cle arance was attributed to the liver. The plasma concentrations of the f our known metabolites of U-54494A were apparently higher for the oral and intraportal routes compared to that after intravenous administrati on. This investigation confirms that the low oral bioavailability of U -54494A in the rat can be primarily attributed to both extensive intes tinal and hepatic first-pass metabolism.