Enantiomer disopyramide

Lima JJ (1988) Species-dependent binding of disopyramide enantiomers. Drug Metabolism Disposition 16 563... 

J. J. Lima, Interaction of disopyramide enantiomers for sites on plasma protein. Life Sci., 41 2807 (1987). 

P. Le Corre, D. Gibassier, E Sado, and R. Le Verge, Stereoselective metabolism and pharmacokinetics of disopyramide enantiomers in humans. Drug Melab. Dispos., 16 858 (1988). 

Takahashi, H. Ogata, H. Shimizu, M. Hashimoto, K. Mashuhara, K. Kashiwada, K. Someya, K. Comparative pharmacokinetics of unbound disopyramide enantiomers following oral administration of racemic disopyramide in humans. J. Pharm. Sci. 1991, 80 (7), 709-711. 

Some of the macrolide antibiotics have been reported to inhibit the clearance of disopyramide (SEDA-21, 200) (SEDA-22, 207), resulting in serious dysrhythmias or hypoglycemia. The mechanism of this interaction is presumed to be inhibition of dealkylation of disopyramide to its major metabolite, mono-A-dealkyldisopyramide. For example, in human liver microsomes the macrolide antibiotic troleandomycin significantly inhibited the mono-A-dealkylation of disopyramide enantiomers by inhibition of CYP3A4 (34). This interaction can result in serious dysrhythmias or other adverse effects of disopyramide. 

Echizen H, Tanizaki M, Tatsuno J, Chiba K, Berwick T, Tani M, Gonzalez FJ, Ishizaki T. Identification of CYP3A4 as the enzyme involved in the mono-N-dealkylation of disopyramide enantiomers in humans. Drug Metab Dispos 2000 28(8) 937 4. 

Kidwell, G. A., Lima, J. J., Schaal, S. F., Muir, W. M. Hemodynamic and electrophysiologic effects of disopyramide enantiomers in a canine blood superfusion model. J. Cardiovasc. Pharmacol. 1989, 13, 644-655. 

Lima, J. J., Boudoulas, H., Shields, B. J. Stereoselective phamacoki-netics of disopyramide enantiomers in man. Drug Metab. Dispos. 1985,13, 572-577. 

H. Takahashi, H. Ogata, and Y. Seki, Binding interaction between enantiomers of disopyramide and mono-N-dealkyldisopyramide on plasma protein, Drug Melab. Dispos., 19 554 (1991). 

Interestingly, the secondary effects of enantiomers may be masked by the presence of their antipodes and only surface after the therapeutic and toxicity properties of the enantiomers are compared with their respective racemate. For example, enantiomers of disopyramide illicit equal antiarrhythmic effects, but the S enantiomer possesses a greater extent of anticholinergic side-effects (12). Intuitively, a formulation composed of the R enantiomer would seem to be a safer alternative. However, it appears that the single enantiomer of disopyramide possesses additional side-effects that are minimal after administration of the racemic drug. 

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... 

Identical chemical and physical properties of enantiomers represent a potential source for enantiomer-enantiomer interactions at both pharmacokinetic and pharmacodynamic levels. Whether by competition for plasma- or tissue-binding sites or for drug-metabolizing enzymes, enantiomers may exhibit changes in pharmacokinetics when administered as a racemate compared to individual stereoisomers. The enantiomers of disopyramide exhibit similar clearance and volumes of distribution when given separately. " However, when administered as the racemate, the 5... 

Fig. 3 Chromatograms showing analysis of disopyr-amide and mono-A -dealkyldisopyramide enantiomers in plasma (A) blank plasma, (B) plasma spiked with 625 ng/ml of disopyramide and mono-A-dealkyldiso-pyramide enantiomers, (C) plasma sample from a healthy volunteer collected 6 hr after administration of 100 mg of Dicorantil. Peak assignments 1, (5)-(+)-disopyramide 2, )-disopyramide 3,4, metoprolol 5, (5 )-(+)-mono-iV -dealkyldisopyramide and 6, (/ )-(—)-mono-A-dealkyldisopyramide. Chromatographic conditions Chiralpak AD column (250 x 4.6 mm I.D., 10 pm particle size) hexane-ethanol (91 9, v/v) mobile phase plus 0.1% diethylamine 1.2ml/min flow rate and detection at 270 nm. (From Ref 1)...

A commercial CE system and a micropacked capillary was used to separate N—, O—, and S-containing heterocyclic compounds. Migration time reproducibility, linearity, and detector response was found to be comparable to HPLC. A study of the heterocyclic compound s elution order followed that predicted by the octanol-water partition coefficients (354). While chiral CEC provides improved resolution and higher efficiencies, additional work is needed since chiral CEC capillaries are not available commercially. The separation principles and chiral recognition mechanism for the separation of enantiomers have been reviewed (355). Furthermore, a comprehensive collection of drug applications and other compounds of interest has been reported (356). Direct enantiomeric separations by CEC were studied using a capillary packed with alpha-1-acid glycoprotein chiral stationary phase (357). Chiral resolution was achieved for enantiomers of benzoin, hexobarbital, pentobarbital, fosfamide, disopyramide, methoprolol, oxprenolol, and propanolol. The effects of pH, electrolyte concentration, and con-... 

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