THE DISPOSITION OF VENLAFAXINE ENANTIOMERS IN DOGS, RATS, AND HUMANS RECEIVING VENLAFAXINE

A stereospecific high-performance liquid chromatographic (HPLC) method was developed for the quantitation of the enantiomers of venlafaxine, an antidepressant, in dog, rat, and human plasma. The procedure invol ves derivatization of venlafaxine with the chiral reagent, (+)-S-napro xen chloride, and a postderivatization procedure. The method was linea r in the range of 50 to 5,000 ng of each enantiomer per ml of plasma. No interference by endogenous substances or known metabolites of venla faxine occurred. Studies to characterize the disposition of the enanti omers of venlafaxine were conducted in dog, rat, and human, following oral administration of venlafaxine. The C(max), area under the curve ( AUC) and (S)/(R) concentration ratios of the (R)- and (S)-enantiomers were compared. In rats, the mean plasma ratio of (S)-venlafaxine to th at of (R)-venlafaxine over 0.5 to 6.0 h varied from 2.97 to 8.50 with a mean value of 5.51 +/- 2.45. The C(max), AUC0-infinity, and t1/2 val ues of the (R)- and (S)-enantiomers in dogs were not significantly dif ferent from one another (P > 0.1). The mean ratios [(S)/(R)] of enanti omers of venlafaxine in human over a 2 to 6 h interval ranged from 1.3 3 to 1.35 with an overall ratio of 1.34 +/- 0.26 (n = 12). These ratio s of the enantiomers [(S)/(R)] were not statistically different from u nity (P > 0.1) indicating that the disposition of venlafaxine enantiom ers in humans is not stereoselective and is more similar to that in do gs than that in rats.