R-Disopyramide

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... 

Hasegawa J, Mori A, Yamamoto R, Kinugawa T, Morisawa T, Kishimoto Y. Disopyramide decreases the fasting serum glucose level in man. Cardiovasc Drugs Ther 1999 13(4) 325-7. 

After a single oral dose of 100 mg of disopyramide phosphate to 6 subjects, peak plasma concentrations of 1.8 to 3.6 pg/ml (mean 2.7) were attained in about 2 hours (R. E. Ranney er a/., Archs int. Pharmacodyn. Ther., 1971, 191, 162-188). 

In a fatality due to the ingestion of about 15g of disopyramide, the following postmortem tissue concentrations were reported blood 57 pg/ ml, brain 29 pg/g, liver 115pg/g, urine 1500pg/ml (R. W. Michalek et ai, J. analyt. Toxicol., 1982, 6, 255-257). 

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... 

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). 

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. 

Upton, R.A. Williams, R.L. The impact of neglecting nonlinear plasma-protein binding on disopyramide bioavailability studies. J. Pharmacokinet. Biopharm. 1986,14 (4), 365-379. 

In vitro studies suggest that the benehcial antiarrhyth-mic properties of disopyramide are concentrated in the S(+)-isomer whereas the negative inotropic effect predominates in the R(-)-isomer. In addition, the pharmacokinetics (clearance and protein binding) differ. For these reasons, selection of the S(+) isomer may have led to the development of a very effective drug with signihcantly fewer therapeutic problems. 

ADM INI STERI NG DISDPYRAMID E Disopyramide is administered to tlie patient witli a full lass of water eitlier 1 hour before or 2 hours after meals. If jiatieiits are receiving procainamide or quinidine tlie manufacturer su ests tliat disopjrramide tlierapy not be started for 6 to 12 hours after tlie last dose of quinidine and 3 to 6 hours after tlie last dose of procainamide When tlie jiatieiit is to switch from taking tlie r ilar cajisules to taking extended-release cajisules, 6 hours should lajise after tlie last cajisule before tlierapy is b in witli tlie extended-release cajisules. 

Hinderling PH, Bres J and Garrett ER, Protein binding and erythrocyte partiticming of disopyramide and its monodealkylated metabolite, /. Pharm. ScL, 63, 1684 (1974). NB This paper r orted p 2 = 10.45, also from the Parke and Davis differential method. 

Table 10 Stereoselective Pharmacokinetics (Mean SD) of Disopyramide after Intravenous Administration of the Individual Enantiomers (R or S) or the Racemate (RS)... 

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