Disopyramide pharmacokinetics

Pharmacokinetics. Disopyramide is used orally (see Table 24.1) and is well absorbed. It is partly excreted unchanged and partly metabolised. The tj is 6 h. 

Although AGP is the most quantitatively important protein in the plasma binding of many basic drugs, it usually exhibits only low enantio-selectivity. This may have measurable pharmacokinetic and pharmacodynamic consequences, as is the case with, for instance, disopyramide, verapamil, and the p-blockers. More generally, however, clinically important effects due to enantioselective binding of drugs to AGP are much less frequently observed than for HSA. 

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). 

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. 

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... 

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. 

In renal insufficiency there are complex changes in the pharmacokinetics of disopyramide, but the overall effect is accumulation of it and its active metabolite, due to reduced renal clearance (28). 

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. 

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

Table 11 Stereoselective Pharmacokinetics (MeaniSD) of Unbound and Total (Bound plus Free) Disopyramide in Humans After Single Oral Doses (lOOmg) of the Racemate... 

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

Giacomini,K.M. Nelson, W.L. Pershe,R. A. Valdivieso,L. Turner-Tamiyasu, K. Blaschke, T.F. In vivo interaction of the enantiomers of disopyramide in human subjects. J. Pharmacokinet. Biopharm. 1986,14,335-356. 

A single 11-g dose of an aluminium phosphate antacid had no statistically significant effect on the pharmacokinetics of a single 200-mg oral dose of disopyramide in 10 patients. However the antacid appeared to reduce the absorption of disopyramide to some extent in individual subjects. The clinical importance of this interaction is uncertain, but probably small. 

Karim A, Nissen C, Azamoff DL. Clinical pharmacokinetics of disopyramide. J Pharmacoh-inet Biopharm (1982) 10, 465-94. 

In contrast, studies in healthy subjects have shown that the negative inotropic elfect was no greater when oral propranolol and disopyramide were used concurrently, nor were the pharmacokinetics of either drug affected. ... 

A single-dose study has shown that cimetidine can slightly increase the serum levels of oral disopyramide. Cimetidine did not affect the pharmacokinetics of intravenous disopyramide. Ranitidine appears not to interact with disopyramide. 

Not fully established. An in vitro study using human liver microsomes indicated that erythromycin inhibits the metabolism (mono-A-dealkylation) of disopyramide which, in vivo, would be expected to reduce its loss from the body and increase its serum levels. Clarithromycin and azithromycin probably do the same. The increased serum levels of disopyramide can result in adverse effects such as QT prolongation and torsade de pointes, and may result in enhanced insulin secretion and hypoglycaemia. - Both intravenous erythromycin and clarithromycin" alone have been associated with prolongation of the QT interval and torsade de pointes. Therefore, disopyramide and macrolides may have additive effects on the QT interval in addition to the pharmacokinetic interaction. 

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