Clinical Pharmacokinetics of Propafenone

Abstract

Propafenone is a class 1C antiarrhythmic agent which is administered as a racemate of S(+)- and R(-)-enantiomers. It is well absorbed and is predominantly bound to alpha 1-acid glycoprotein in the plasma. The enantiomers display stereoselective disposition characteristics, the R-enantiomer being cleared more quickly. The hepatic metabolism of propafenone is polymorphic and genetically determined: about 10% of Caucasians have a reduced capacity to hydroxylate the drug. This polymorphic metabolism accounts for the marked interindividual variability in the relationships between dose and concentration, and between concentration and pharmacodynamic effects. During long term administration, the metabolism is saturable in patients with the 'extensive metaboliser' phenotype, leading to accumulation of the parent compound. Propafenone blocks fast inward sodium channels in a frequency-dependent manner, and also has moderate beta-blocking effects. Both the enantiomers and the 5-OH metabolite have a potency to block sodium channels comparable with that of the parent compound. The S-enantiomer is a more potent beta-antagonist than the R-enantiomer. Propafenone typically slows conduction markedly but only modestly prolongs refractoriness. These cardiac effects are determined by the extent of its myocardial accumulation. The drug should be used with caution in patients with serious structural heart disease, as it may cause or aggravate life-threatening arrhythmias. Significant interactions occur when propafenone is coadministered with other drugs. It increases the plasma concentrations of digoxin, warfarin, metoprolol and propranolol as well as enhancing their respective pharmacodynamic effects. Doses of these drugs should therefore be decreased if they are coadministered with propafenone.

Capillary electrophoretic investigation of the enantioselective metabolism of propafenone by human cytochrome P‐450 SUPERSOMES: Evidence for atypical kinetics by CYP2D6 and CYP3A4

“…This relationship holds for incubations with racemic PPF and individual PPF enantiomers. As CYP2D6 and CYP3A4 showed the highest contribution to PPF 5-hydroxylation and N-dealkylation, respectively, the stereoselective kinetics of PPF hydroxylation and dealkylation in media containing CYP2D6 and CYP3A4 SUPERSOMES was further investigated to gain more clues about the stereoselective clearance of PPF ,which has been reported in vivo [5,6]. To accurately determine kinetic parameters, substrate consumption at all concentrations of substrates was controlled to be less than 15%, and production of metabolites used for quantification of formation rates was linear with incubation time and protein concentration.…”

“…It has been shown that PPF ring hydroxylation is under genetic control and cosegregates with the debrisoquine metabolic phenotype. After oral administration of PPF, R-PPF has been shown to have a higher clearance than its antipode, suggesting that PPF is metabolized stereoselectively in vivo [5,6]. Given the stereoselective pharmacodynamic and disposition characteristics of PPF and its specific biotransformation, identification of human CYP isoforms involved in its metabolism and investigation of their enantioselective kinetic profiles has attracted considerable interest.…”

Validated capillary electrophoresis assay for the simultaneous enantioselective determination of propafenone and its major metabolites in biological samples

“…The enantiomers of PPF were found to display stereoselective pharmacodynamic, distribution, and elimination characteristics. Although equipotent in the sodium channel-blocking activity, S-PPF is almost 100 times more potent at b-adrenergic receptors [4,6]. In terms of distribution, the free fraction of the R-isomer is higher than that of the S-isomer.…”

“…In humans, PPF is extensively metabolized by ring hydroxylation, as the dominant metabolic pathway, and N-dealkylation, leading to pharmacologically active 5-hydroxy-propafenone (5OH-PPF) and N-despropyl-propafenone (norpropafenone, NOR-PPF), respectively. Hydroxylation is catalyzed by the polymorphically expressed cytochromal enzyme CYP2D6, such that poor metabolizers can be distinguished from extensive metabolizers, while, N-dealkylation is known to be mediated via CYP3A4 and CYP1A2 [4,5]. The enantiomers of PPF were found to display stereoselective pharmacodynamic, distribution, and elimination characteristics.…”

The influence of CYP2D6 activity on the kinetics of propafenone enantiomers in Chinese subjects

“…The purpose of this study and R-PPF [1]. The two enantiomers are metabolized at different rates in Caucasians, with the R-PPF being was to examine the dispositon of propafenone enantiomers in 16 EMs and one PM to determine if stereoselective eliminated faster than the S-PPF [2].…”