Verapamil potency

The important paradoxical finding that verapamil potency depends on route of administration (intravenous vs. oral) also holds when dissimilar oral formulations are compared. The paradox is avoided by using a stereospedfic assay to follow enantiomer concentrations and to associate the effect with concentrations of the appropriate enantiomer(s). Both the route of administration and type of oral formulation are important influences on the relative systemic concentrations of the two enantiomers. In addition, the amount of time elapsed post-dose, the amount of verapamil administered, and whether a single dose or chroiuc dosing is involved also have a major impact on the enantiomer ratio. 

Important differences in vascular selectivity exist among the calcium channel blockers. In general, the dihydropyridines have a greater ratio of vascular smooth muscle effects relative to cardiac effects than do diltiazem and verapamil. Furthermore, the dihydropyridines may differ in their potency in different vascular beds. For example, nimodipine is claimed to be particularly selective for cerebral blood vessels. Splice variants in the structure of the cq channel subunit appear to account for these differences. 

The choice of a cell line to study MDR modulator potency was very important for future potential application in human cancer treatment. PhM (12) that were quite effective in resistant mouse lymphoma cells were only slightly active in drug-resistant human sarcoma cell line MES-SA/Dx5 [198]. The drug-sensitive human sarcoma cell line MES-SA and its multidrug-resistant counterpart MES-SA/Dx5 were applied as a model system for evaluation of MDR modulator activities. Examination performed by the flow cytometric Rhl23 accumulation test demonstrated that the well-known P-gp modulators verapamil (79) and TFP (5) reduced MDR in MES-SA/Dx5 cells. In resistant MES-SA/Dx5 cells, verapamil (79) and TFP (5) restored the drug accumulation pattern which was typical for sensitive cells. However, the effectiveness of PhM (12) was very low. The most active compounds were derivatives with an H atom at position 2 of the phenothiazine ring, followed by Cl-substituted and CF3-substituted compounds. 

Analogues of verapamil (1) were also studied for their calciiun channel antagonist activity, and their potency for isotonic contractile response of cat capillary muscle preparation was reported [30], which was foimd to be correlated with the electronic constant and the molecular volume of the B-ring substituents as ... 

The two stereoisomers of verapamil differ extensively in their pharmacodynamics. The S enantiomer is the more pharmacologically active of the two relative to the cardiovascular system (3,6-9). The cardiovascular pharmacod maniic effects and relative potency of S- and R-verapamil are summarized in Table 1. 

Table 1 Summary of the Pharmacodynamic Effects of Verapamil and Relative Potencies of the S and R Enantiomers...

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