The pharmacokinetics of (+)‐, (‐)‐, and (+/‐)‐verapamil were studied in five healthy volunteers following i.v. administration of the drugs. Pronounced differences of the various pharmacokinetic parameters were observed between the (‐)‐ and (+)‐isomers. The values for CL, V, Vz, and Vss of the (‐)‐isomer were substantially higher as compared to the (+)‐isomer, whereas terminal t 1/ 2Z was nearly identical for both isomers. No dose dependency of the pharmacokinetics could be observed in two subjects who received 5, 7.5 and 10 mg of (‐)‐ and 5, 25 and 50 mg of (+)‐verapamil. Protein binding for the two isomers was also different. The fu of (‐)‐ (0.11) was almost twice as much as that of (+)‐verapamil (0.064). Pharmacokinetic parameters of (+/‐)‐verapamil, which was administered to three subjects who had received (+)‐ and (‐)‐ verapamil, were very similar to the averaged values of the isomers given separately. Due to the higher CL of (‐)‐verapamil the extraction ratio of the (‐)‐isomer is substantially higher. Thus, it can be anticipated that following oral administration of racemic verapamil bioavailability of (‐)‐verapamil will be substantially less. Since the (‐)‐isomer is more potent than the (+)‐isomer, the present findings could explain the reported differences in the concentration‐effect relationship after i.v. and oral administration of racemic verapamil.

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The pharmacokinetics of dextro(+)‐ and levo(‐)‐verapamil were studied in five healthy volunteers following oral administration of pseudoracemic verapamil containing equal amounts of unlabelled (‐)‐ and dideuterated (+)‐isomer. (+)‐verapamil exhibited approximately five times greater Cmax (+): 240 +/‐ 81.1 ng/ml, (‐): 46.1 +/‐ 15.7 ng/ml, P less than 0.0001) and AUC than (‐)‐verapamil. The apparent oral clearance (CLo) for (+)‐verapamil was significantly smaller than that for (‐)‐verapamil (+): 1.72 +/‐ 0.57 l/min, (‐): 7.46 +/‐ 2.16 l/min, P less than 0.001). The bioavailability of (+)‐verapamil (50%) was 2.5 times greater than that of (‐)‐verapamil (20%), P less than 0.005). Thus following oral administration verapamil exhibited a stereoselective first‐pass metabolism. Neither tmax nor the elimination t1/2,z were different between the isomers. The elimination of t1/2,z for each verapamil isomer obtained following oral administration (+): 4.03 h, (‐): 5.38 h) were similar to those previously obtained following intravenous administration (+): 4.15 h, (‐): 5.38 h, respectively. Whereas the (+)‐ to (‐)‐verapamil plasma concentration ratio following oral administration was 4.92 +/‐ 0.48, the ratio following i.v. administration was approximately 2. (‐)‐verapamil has been demonstrated to possess 8 to 10 times more potent negative dromotropic effect on AV conduction than (+)‐verapamil. Therefore, following oral administration the same concentration of plasma verapamil consisting of a two to three times smaller proportion of the more potent (‐)‐isomer appeared to be less potent than that following i.v. administration with regard to the negative dromotropic effects on the AV conduction.

After the oral administration of 160 mg pseudoracemic verapamil (80 mg dideuterodextro (d) isomer and 80 mg levo (l) isomer), the prolongation of the PR interval was assessed in relation to d- and l-verapamil plasma concentrations. Concentration-effect curves were analyzed with the sigmoidal Emax model. Because of stereoselective first-pass metabolism, the mean plasma d- to l-verapamil concentration ratio of 4.5 +/- 1.2 was substantially greater than that of 2.1 +/- 0.3 after intravenous dosing. Compared with the concentration after intravenous injection, the total verapamil concentration after oral dosing consisted of a substantially smaller proportion of the more potent l-isomer. These differences in isomer composition of the total verapamil plasma concentration as a result of the route of administration explain the diminished negative dromotropic potency of racemic verapamil after oral dosing. The concentration required to reach 50% of the maximum effect (EC50) for total verapamil concentration was 129.0 +/- 22.9 ng/ml, which was more than three times higher than that after intravenous injection. To assess the relative contributions of the d- and l-isomers to overall dromotropic potency, changes in the PR interval were measured after separate oral dosing with 250 mg d-verapamil and 100 mg l-verapamil. The EC50 showed an 11-fold difference between the l- (36.9 +/- 14.7 ng/ml) and d- (363.1 +/- 64.2 ng/ml) isomers. The EC50 for the l-isomer concentration after oral pseudoracemic verapamil (20.2 +/- 6.3 ng/ml) did not differ significantly from that after l-verapamil alone (36.9 +/- 14.7 ng/ml). We conclude that the l-isomer determines the negative dromotropic effects of verapamil and that the d-isomer is of minor importance.

Most of adult women exhibit cellulite on the hips, buttock and thighs. Although extracellular matrix and lymphatic system disorders can increase its appearance, cellulite basically results from an excessive fat storage in the adipose tissue which exerts considerable pressure on the surrounding skin tissue and creates a dimpled irregular appearance. Caffeine, the most widely used anti-cellulite ingredient, favours fat break-down by inhibiting the phosphodiesterase enzyme and encouraging a high intracellular level of cAMP. A series of studies has shown that spermine and spermidine, two ubiquitous polyamines, encouraged fat storage and slowed fat break-down in the adipose tissue. Besides, it was shown that heparan sulfate glycosaminoglycans had a strong affinity for polyamines. To design a new cosmetic ingredient with anti-cellulite properties, we used molecular modelling to screen several ingredients with a structure similar to that of heparan sulfate glycosaminoglycans. This way, we identified sulfo-carrabiose as a potent molecule for trapping spermine and spermidine. These virtual results were first confirmed in tubo where sulfo-carrabiose was shown to dose-dependently inactivate spermine and spermidine. In vitro, adipocytes cultured with sulfo-carrabiose exhibited a significant reduction of lipogenesis and a significant increase of lipolysis. When sulfo-carrabiose was incorporated in a cosmetic formula, significant improvements were observed in thigh circumference, with better results than those obtained with caffeine after 28 days of use. Furthermore, a combination of caffeine and sulfo-carrabiose led to results significantly better than those obtained with caffeine alone. As measured by fringe projection, thigh volume was also significantly reduced after sulfo-carrabiose treatment. Finally, the appearance of cellulite assessed by clinical evaluation was also significantly reduced within 28 days.