PHARMACOKINETICS OF THE ENANTIOMERS OF VERAPAMIL IN THE DOG

The intravenous (0.5 mg/kg) and oral (5 mg/kg) dose kinetics of verapa mil were studied in 6 dogs during steady-state oral verapamil dosing ( 5 mg/kg every 8 h for 3 days). Racemic verapamil and norverapamil, a m etabolite of verapamil, were quantitated in plasma by HPLC-fluorescenc e detection. The verapamil peaks eluting off the column were collected and rechromatographed on an Ultron-OVM column, which resolved the two verapamil enantiomers. After intravenous administration, the systemic clearance and apparent volume of distribution of (-)-(S)-verapamil we re nearly twice that of the (+)-(R)-isomer. There was no difference in the elimination half-lives between the two isomers. After oral admini stration, the oral clearance of (-)-(S)-verapamil was 20 times that of the (+)-(R)-isomer. The apparent bioavailability of (+)-(R)-verapamil was over 14 times that of (-)-(S)-verapamil. The plasma protein bindi ng of the (+)-(R)-isomer was slightly higher by 5% than (-)-(S)-verapa mil; however, this effect was not enough to account for the difference between the apparent volume of distribution of the enantiomers, indic ating that the tissue binding of (-)-(S)-verapamil was greater than th at of the (+)-(R)-isomer. This data on the disposition of the enantiom ers of verapamil in the dog is similar to that reported for man and de monstrates that the dog may be an appropriate animal model for man in future studies on the disposition of the enantiomers of verapamil. (C) 1993 Wiley-Liss, Inc.