PHARMACOKINETICS OF VERAPAMIL AND NORVERAPAMIL ENANTIOMERS AFTER ADMINISTRATION OF IMMEDIATE AND CONTROLLED-RELEASE FORMULATIONS TO HUMANS - EVIDENCE SUGGESTING INPUT-RATE DETERMINED STEREOSELECTIVITY

Verapamil is a racemic calcium channel-blocking drug that undergoes ex tensive hepatic first-pass metabolism to an active metabolite, norvera pamil. The enantiomers of verapamil and norverapamil have differing ne gative inotropic, chronotropic, and dromotropic activities and differi ng effects on vascular smooth muscles; the S-enantiomers having greate r activity. It is hypothesized that the R/S concentration ratio of ver apamil enantiomers may be input-rate dependent. The pharmacokinetics o f verapamil and norverapamil enantiomers were studied in 11 young, hea lthy male and female volunteers after oral administration of 80 mg imm ediate-release (IR) verapamil every 8 hours, and a 240 mg dose once da ily of controlled-release (CR) formulation on two separate occasions. Both dosage regimens were continued for 1 week with a minimum 1-week p eriod between the two drug treatments. After the last dose of each reg imen, plasma samples were collected over the period corresponding to t he dosing interval. Enantiomer concentrations were determined using a microwave-facilitated precolumn derivatization with high performance l iquid chromatographic quantification. Stereospecific assay revealed th at: (1) stereoselective R- and S-enantiomer disposition occurred regar dless of formulation administered; (2) a trend of R:S concentration ra tios of verapamil differed between the two formulations; and (3) fluct uations between C-max and C-min values of the two formulations were st atistically different over respective dosing intervals (greater fluctu ation after CR administration). Using nonstereospecific data analyses, however, the pharmacokinetic parameters for verapamil and norverapami l were similar for both formulations over a 24-hour period. We suggest that kinetic differences can be attributed to differences in release rates of drug from the tablet matrices. The relative bioavailabilities of verapamil and norverapamil from the two products may, therefore, b e subject to input rate-dependent processes.