The Role of Genetically Determined Polymorphic Drug Metabolism in the Beta-Blockade Produced by Propafenone

Abstract

Propranolol and the sodium-channel-blocking antiarrhythmic agent propafenone share structural features. Although propafenone's beta-blocking actions are readily demonstrable in vitro, clinically significant beta-blockade occurs inconsistently in vivo. In this study, we tested the hypothesis that genetically determined variations in the biotransformation of propafenone to its 5-hydroxy metabolite account for variations in the drug's beta-blocking action. We assessed beta-blockade by measuring the reduction in tachycardia produced by boluses of isoproterenol and treadmill exercise in 14 normal subjects during treatment with placebo and with 150, 225, and 300 mg of propafenone every eight hours for five days each. Nine subjects (with the extensive-metabolizer phenotype) metabolized most of the propafenone to 5-hydroxy propafenone, and five (with the poor-metabolizer phenotype) did not produce this metabolite. At the lower dosages, beta-blockade was present in both groups but was significantly greater in the subjects with poor metabolism, in whom deficient 5-hydroxylation was associated with higher plasma propafenone levels. At the highest dose, a similar degree of beta-blockade was observed in the two groups. Propafenone also had a higher affinity for beta 2 receptors in vitro than either of its major metabolites. We conclude that the degree of beta-blockade during propafenone therapy reflects genetically determined variations in the metabolism of the parent drug, which is necessary for beta-blockade, and that this action of propafenone is considerably enhanced in patients with deficient 5-hydroxylation of propafenone.

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

“…CYP2D6 status is generally thought to matter little for antiarrhythmic effect (Siddoway et al, 1987;Labbe et al, 2000), although some studies have suggested greater efficacy in those with reduced CYP2D6 activity (Jazwinska-Tamawska et al, 2001;Cai et al, 2002). PMs may be predisposed to more central nervous system adverse effects (76 versus 14% in EMs) (Siddoway et al, 1987) and greater ␤-blockade (Lee et al, 1990;Morike and Roden, 1994), although the latter result has been contradicted (Labbe et al, 2000). There is a case report of toxicity (dizziness and bradycardia) in a PM (Morike et al, 1995).…”

“…The propafenone/ 5-hydroxypropafenone ratio correlates with the debrisoquine metabolic ratio . PMs have 3-to 7-fold higher propafenone AUCs at steady state than EMs and produce very low or negligible concentrations of 5-hydroxypropafenone (Siddoway et al, 1987;Kroemer et al, 1989a;Lee et al, 1990;Dilger et al, 1999;Labbe et al, 2000). CYP2D6 status is generally thought to matter little for antiarrhythmic effect (Siddoway et al, 1987;Labbe et al, 2000), although some studies have suggested greater efficacy in those with reduced CYP2D6 activity (Jazwinska-Tamawska et al, 2001;Cai et al, 2002).…”

Proarrhythmia

“…This is generally not clinically significant. The parent molecule does have β-blocking activity, whereas the metabolite does not, and so adverse effects due to β-blockade are more common with the deficient CYP2D6 activity (Lee et al 1990). Flecainide is also a CYP2D6 substrate but is also excreted unchanged by the kidneys.…”

Proarrhythmia as a pharmacogenomic entity: A critical review and formulation of a unifying hypothesis

“…& The antiarrhythmic propafenone is eliminated by metabolism through the cytochrome P450 CYP2D6, and in individuals with deficient CYP2D6 activity, parent drug accumulates and side effects, including bradycardia (likely due to beta blockade) are common [12,13]. CYP2D6 activity is absent in 7% of Caucasians and African -Americans (''poor metabolizers'') because they are homozygous for loss of function alleles, dozens of which have now been described (http://www.imm.ki.se/ CYPalleles/).…”