PHARMACOKINETICS OF THE ENANTIOMERS OF VERAPAMIL AFTER INTRAVENOUS AND ORAL-ADMINISTRATION OF RACEMIC VERAPAMIL IN A RAT MODEL

Verapamil is a chiral calcium channel blocking drug which is useful cl inically as the racemate in treating hypertension and arrhythmia. The published pharmacokinetic data for verapamil enantiomers in the rat mo del are limited. Utilizing a stereospecific highperformance liquid chr omatographic (HPLC) assay, the enantiomeric disposition of verapamil i s reported after intravenous (1.0 mg kg(-1)) and oral (10 mg kg(-1)) a dministration of racemic verapamil to the rat model. After intravenous administration the systemic clearance of R-verapamil was significantl y greater than that of S-verapamil; 34.9 +/- 7 against 23.7 +/- 3.7 mL min(-1) kg(-1) (mean +/- SD), respectively. After oral administration , the clearance of R-verapamil was significantly greater than that of S-verapamil, 889 +/- 294 against 351 +/- 109 mL min(-1) kg(-1), respec tively. The apparent oral bioavailability of S-verapamil was greater t han that of R-verapamil, 0.074 +/- 0.031 against 0.041 +/- 0.011, resp ectively. These data suggest that the disposition of verapamil in the rat is stereoselective; verapamil undergoes extensive stereoselective first-pass clearance after oral administration and the direction of st ereoselectivity in plasma is opposite to that observed in the human. ( C) 1997 by John Wiley & Sons, Ltd.