Pharmacokinetics of the individual enantiomers of cis-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzamide monohydrochloride (U-54494A) in the dog.

U-54494A, a racemic mixture of two enantiomers, is being developed in racemic form as an anticonvulsant drug candidate. A comparative pharmacokinetic study with intravenous and oral administration of the two individual enantiomers to the dog was conducted to evaluate the potential enantioselective pharmacokinetics of U-54494. Following i.v. administration, the (-)- and (+)-enantiomers showed no significant differences in plasma clearance (0.84 +/- 0.11 versus 0.86 +/- 0.06 l/hr/kg) and terminal elimination half-life (11.2 +/- 2.7 versus 8.0 +/- 2.6 hr) for the parent drug. However, the AUC of intact drug was two-fold lower with two-fold shorter elimination half-life following the oral administration for the (+)-enantiomer as compared to the (-)-enantiomer. Higher plasma levels of the four metabolites were also observed for the (+)-than for the (-)-enantiomer, particularly after oral administration. These results suggested that the (+)-enantiomer appeared to be more extensively metabolized by first-pass effect than the (-)-enantiomer after oral dosing, and as a result, oral bioavailability for the (+)-enantiomer is only one half of that for its antipode (12.0 +/- 1.5% versus 26 +/- 9%).

First-pass effect of cis-3,4-dichloro-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 relative contribution of the gut and liver as sites of first-pass metabolism of orally administered U-54494A, an anticonvulsant drug candidate. Each rat received a dose of U-54494A by oral, intraportal, and intravenous routes on three separate occasions. Intraportal and intravenous doses were administered through chronic cannulas surgically implanted in the portal vein and superior vena cava, respectively. Blood samples were collected over a 6-hr period from the superior vena cava cannula. The 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 contribution 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 clearance was attributeds to the liver. The plasma concentrations of the four known metabolites of U-54494A were apparently higher for the oral and intraportal routes compared to that after intravenous administration. This investigation confirms that the low oral bioavailability of U-54494A in the rat can be primarily attributed to both extensive intestinal and hepatic first-pass metabolism.