The influence of cimetidine on the pharmacokinetics of the enantiomers of verapamil in the dog during multiple oral dosing

The disposition of intravenously (0.5 mg/kg) and orally (5 mg/kg) administered verapamil was studied in six dogs after 3 days' pre-treatment with verapamil alone (5 mg/kg, every 8 h) and during concomitant oral administration of cimetidine (16 mg/kg, every 8 h). Racemic verapamil and norverapamil, an active metabolite of verapamil, were measured by fluorescence high performance liquid chromatography using an achiral phenyl column. The isolated racemic verapamil was rechromatographed on an Ultron-OVM chiral column, which separated the two verapamil enantiomers. Cimetidine co-administration significantly reduced the systemic clearance of racemic verapamil as well as that of its enantiomers by 25–29%. The clearance of racemic verapamil administered orally as well as that of its enantiomers was also reduced by 28% during cimetidine coadministration. The decrease in verapamil metabolism by cimetidine appeared to be non-stereoselective. On the other hand, cimetidine co-administration had no significant effect on the apparent volume of distribution of racemic verapamil and its enantiomers or the plasma protein binding or the blood to plasma concentration ratio of racemic verapamil. In addition, the ratio of the area under the plasma concentration-time curve for norverapamil to that of verapamil was unaffected by cimetidine co-administration. These results suggest that cimetidine alters the disposition of verapamil by decreasing the hepatic blood flow rate and by inhibition of its first-pass metabolism.