Verapamil isomers

All five major chiral stationary phases have a very wide range of applications. Nevertheless, the selectivity that they achieve is sometimes limited and the separation ratios of the enantiomers small. As a consequence, relatively high efficiencies are usually necessary to achieve the desired resolution. Examples of the use of the popular protein stationary phases are the separation of the Verapamil isomers, and the epibatidine and vamicamide enantiomers. These chiral stationary phases have also been used to separate optical isomers of a leukotriene antagonist. The Pirkle chiral stationary phases are also very well-liked as... 

Verapamil. Verapamil hydrochloride (see Table 1) is a synthetic papaverine [58-74-2] C2qH2 N04, derivative that was originally studied as a smooth muscle relaxant. It was later found to have properties of a new class of dmgs that inhibited transmembrane calcium movements. It is a (+),(—) racemic mixture. The (+)-isomer has local anesthetic properties and may exert effects on the fast sodium channel and slow phase 0 depolarization of the action potential. The (—)-isomer affects the slow calcium channel. Verapamil is an effective antiarrhythmic agent for supraventricular AV nodal reentrant arrhythmias (V1-2) and for controlling the ventricular response to atrial fibrillation (1,2,71—73). 

Two isomers of teludipine (54), R-enantiomer (GR66234A) and L-cn-antiomer (GR66235 A) which were originally developed as a new lipophilic calcium channel blocker by Glaxo were evaluated for daunorubicin resistance reversal activity and found to be more effective than verapamil. Additionally, the difference in activity was also found on different cells. Verapamil and the enantiomers of teludipine are more active in ARNII cells than in MCF 7/R cells. There were no apparent differences in cellular daunorubicin accumulation between ARNII and MCF 7/R following exposure to teludipine and no differences in intracellular daunorubicin distribution in the presence of either MDR reversing agent were observed [97]. 

Further clinical examples of potential stereoselective renal secretion of organic cations have been recently reported. A major metabolite of verapamil (D-617) is actively secreted by the kidney (59). Upon coadministration of dmetidine, the renal clearance of the S-D-617 isomer was significantly decreased, whereas the clearance of the R-D-617 metabolite was unaffected by dmetidine administration (59). Stereoselective renal secretion was suggested as the mechanism of this effect. However, it is not known if this metabolite is actually secreted by the organic cation transport system. The renal clearance of unbound S(+) disopyramide was... 

K. Satoh, T. Yanagisawa, and N. Taira, Coronary vasodilator and cardiac effects of optical isomers of verapamil in the dog, /. Cardiavasc. Pharmacol., 2 309-318 (1980). 

For enantiomeric drugs with low organ clearance, differences in renal or hepatic clearance between stereoisomers may reflect their free fraction in the plasma and not real stereoselectivity of the ability of the organ to remove the free enantiomers (intrinsic clearance) from the plasma. Clearance differences between stereoisomers of verapamil and disopyramide may be a function of plasma protein binding differences. In addition, volumes of distribution as well as concentration ratios of stereoisomers in body fluids to total plasma and blood are influenced by plasma protein binding. For example, the larger volume of distribution and greater total body clearance of R-disopyramide compared to the S isomer may be explained by the lower... 

Parameter Isomer Warfarin Ibuprofen Disopyramide PropranoF Verapamil ... 

Raschack, M. Relationship of antiarrhythmic to inotropic activity and antiarrhythmic qualities of the optical isomers of verapamil. Arch. Pharmacol. 1976, 294 (3), 285-291. 

In an intestinal perfusion study of the effect of ketoconazole 40 pg/ml on the jejunal permeability and first-pass metabolism of (R)- and (5)-verapamil 120 pg/ml in six healthy volunteers, ketoconazole did not alter the jejunal permeability of the isomers, suggesting that it had no effect on the P-glycoprotein mediated efflux. However, the rate of absorption increased, suggesting inhibition by ketoconazole of the gut wall metabolism of (i /5)-verapamil by CYP3A4 (35). 

Verapamil is a synthetic compound possessing slight structural similarity to papaverine. It can be separated into its optically active isomers, of which the levorotatory enantiomer is the most potent. It is absorbed rapidly after oral administration. The drug is metaboli zed quickly and. as a result, has low bioavailability. The liver is the main site of first-pass metaboli.sm. forming several products. The preferential metabolic step involves N-dealkylation. followed by O-demethylation. and subsequent conjugation of the product before elimination. The metabolites have no significant biological activity. Verapamil has an elimination half-life of approximately 5 hours. 

Many drug compounds are racemic mixtures of stereoisomers. In most cases, one of the isomers is more pharmacologically active than the other isomer, and each isomer may exhibit different pharmacokinetic properties. Warfarin, propranolol, verapamil, and ibuprofen are aU racemic mixtures of stereoisomers. Some drug interactions inhibit or increase the elimination of only one stereoisomer. The importance of the drug interaction depends on which isomer is affected. Other drugs, such as dextromethorphan, levofloxacin, and dUtiazem, are composed of just one stereoisomer. 

Experiments utilizing isolated superfused and blood perfused cardiac tissue preparations and isolated rat, rabbit, and cat whole hearts all demonstrate the potent, concentration-dependent, negative inotropic activity of the calcium inhibitory compounds (45 50, 90-95, 112, 113, 114, 118, 140, 141). Studies comparing the relative negative inotropic effects of several of the calcium inhibitory compounds indicate that those compounds exhibiting the most potent calcium inhibitory effects in vitro are the most effective in reducing cardiac contractility in vivo (6). Of those compounds most frequently compared, nifedipine and niludipine exhibit the most profound negative inotropic activity followed by verapamil (levo isomer), diltiazem and perhexiline (88, 89-142). 

Diltiazem is a known inhibitor of the cytochrome P450 isoenzyme CYP3A4. However, this isoenzyme has only a minor role in the metabolism of warfarin , (p.358), specifically in the metabolism of the less active R-isomer of warfarin. Consequently, only minor increases in the levels of warfarin have been seen in pharmacokinetic studies, which would generally not be expected to be clinically relevant. Verapamil is also an inhibitor of CYP3A4, but the dihydropyridine calcium-charmel blockers ate not. 

Finally, figure 11.13 (F) shows the separation of the isomers of Verapamil on cellulose tris(3,5-difluorophenyl carbamate). In this separation, the mobile phase was -hexane/2-propanol/diethylamine 80/20/0.1 v/v/v. It is seen that adequate separation is achieved and that the peaks are a little more symmetrical, probably because the high activity sites on the exposed silica are blocked by the trace of... 

The layers coated with (—)-vancomycin were also successfully used for the separation of enantiomers of verapamil, a calcium channel blocker usually administered as racemic compound, even though the 5-(—)-isomer was 20-30 times pharmacologically more active than the i -(+)-form [42], The results are reported in Table 5.13. Amounts as low as 0.075 /rg of each enantiomer were detected by iodine vapor at working temperature 18 C. 

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