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%).