No abstract

Verapamil is a chiral calcium channel blocking drug which is useful clinically as the racemate in treating hypertension and arrhythmia. The published pharmacokinetic data for verapamil enantiomers in the rat model are limited. Utilizing a stereospecific high‐performance liquid chromatographic (HPLC) assay, the enantiomeric disposition of verapamil is reported after intravenous (1·0 mg kg−1) and oral (10 mg kg−1) administration of racemic verapamil to the rat model. After intravenous administration the systemic clearance of R‐verapamil was significantly greater than that of S‐verapamil; 34·9 ± 7  against 2·7 ± 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, respectively. The apparent oral bioavailability of S‐verapamil was greater than that of R‐verapamil, 0·074 ± 0·031 against 0·041 ± 0·011, respectively. 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 stereoselectivity in plasma is opposite to that observed in the human. © 1997 John Wiley & Sons, Ltd.

Verapamil is a racemic calcium channel-blocking drug that undergoes extensive hepatic first-pass metabolism to an active metabolite, norverapamil. The enantiomers of verapamil and norverapamil have differing negative inotropic, chronotropic, and dromotropic activities and differing effects on vascular smooth muscles; the S-enantiomers having greater activity. It is hypothesized that the R/S concentration ratio of verapamil enantiomers may be input-rate dependent. The pharmacokinetics of verapamil and norverapamil enantiomers were studied in 11 young, healthy male and female volunteers after oral administration of 80 mg immediate-release (IR) verapamil every 8 hours, and a 240 mg dose once daily of controlled-release (CR) formulation on two separate occasions. Both dosage regimens were continued for 1 week with a minimum 1-week period between the two drug treatments. After the last dose of each regimen, plasma samples were collected over the period corresponding to the dosing interval. Enantiomer concentrations were determined using a microwave-facilitated precolumn derivatization with high performance liquid chromatographic quantification. Stereospecific assay revealed that: (1) stereoselective R- and S-enantiomer disposition occurred regardless of formulation administered; (2) a trend of R:S concentration ratios of verapamil differed between the two formulations; and (3) fluctuations between Cmax and Cmin values of the two formulations were statistically different over respective dosing intervals (greater fluctuation after CR administration). Using nonstereospecific data analyses, however, the pharmacokinetic parameters for verapamil and norverapamil 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, be subject to input rate-dependent processes.

No abstract

No abstract