DRUG DISPOSITION
Clin. Pharmacokinet. 21 (I): 1- 10, 1991 0312-5963/91 /0007-000 I/$05.00/0 © Adis International Limited. All rights reserved. CPK102Sa
Clinical Pharmacokinetics of Propafenone John T. Y. Hii, Henry J. Duff and Ellen D. Burgess Department of Medicine, University of Calgary, Calgary, Alberta, Canada
Contents J 2 2
3 3 5 5 5 5 7 7 7 7
7 7 7 8
8 9
Summary
Summary 1. Basic Pharmacokinetic Profile of Propafenone 1.1 Absorption 1.2 Distribution 1.3 Metabolism and Elimination 2. Electrophysiological Effects of Propafenone 2. 1 In Vitro Effects 2.2 In Vivo Effects 3. Pharmacokinetic-Pharmacodynamic Effects 4. Pharmacokinetics of Propafenone in Disease States 4. 1 Hepatic Dysfunction 4.2 Renal Failure 5. Drug Interactions 5.1 Interaction with Digoxin 5.2 Interaction with Warfarin 5.3 Interaction with Propranolol/Metoprolol 5.4 Interaction with Quinidine 6. Adverse Effects 7. Conclusion
Propafenone is a class IC antiarrhythmic agent which is administered as a racemate of S(+)and R(-)-enantiomers. It is well absorbed and is predominantly bound to ai-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 (j-blocking effects. Both the enantiomers and the 5-0H metabolite have a potency to block sodium channels comparable with that of the parent compound. The S-enantiomer is a more potent (j-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
Clin. Pharmacokinet. 21 (1) 1991
2
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.
1. Basic Pharmacokinetic Profile 0/ Propa/enone 1.1 Absorption
Propafenone is administered as a racemic compound. It can be administered either orally or intravenously; after oral administration, more than 90% of the dose is absorbed (Hege et al. 1984; Hollman et al. 1983) and its peak plasma concentration (Cmax ) is usually reached after about 2h. The bioavailability is dependent on several factors: in general, systemic bioavailability ranges from 5 to 50%, which reflects high presystemic clearance. Coadministration of propafenone with food increases its bioavailability (Axelson et al. 1987) although the mechanism of this phenomenon is uncertain. Also, in the presence of food, Cmax is more rapidly attained. It is interesting that such enhancement of propafenone bioavailability by food could only be demonstrated in subjects with the 'extensive metaboliser' phenotype (see below). The mean increase in area under the concentration-time curve (AUC) was 147% when only extensive metaboliser phenotype subjects were used in the calculation, and 120% when all subject data were incorporated. Propafenone bioavailability is also determined by the dosage form (Hollmann et al. 1983). When administered as a solution, the bioavailability is higher, but it is only about 12% following administration of a 300mg film-coated tablet. Propafenone bioavailability is also dose-dependent, rising as the dose is increased. This is partly due to a decrease in its presystemic clearance (Connolly et al. 1983a; Hollmann et al. 1983). The dose-concentration relationship is not always linear: Hollmann et al. (1983), using single doses of propafenone in healthy volunteers, showed a 6-fold increase in plasma concentration as the oral dose was in-
creased 3-fold. In another study (Connolly et al. 1983a), there was a 10-fold increase in the mean steady state propafenone concentration as the dosage was increased 3-fold (fig. 1). These observations further supported the concept of saturable metabolism for this drug. A more recent study indicates that the nonlinear dose-concentration relationship occurs in subjects with the extensive metaboliser phenotype, suggesting that 5-hydroxylation of propafenone is saturable. In subjects with
1000
~ ..:!. J~ 750
~
(I)
Clin. Pharmacokinet. 21 (I): 1- 10, 1991 0312-5963/91 /0007-000 I/$05.00/0 © Adis International Limited. All rights reserved. CPK102Sa
Clinical Pharmacokinetics of Propafenone John T. Y. Hii, Henry J. Duff and Ellen D. Burgess Department of Medicine, University of Calgary, Calgary, Alberta, Canada
Contents J 2 2
3 3 5 5 5 5 7 7 7 7
7 7 7 8
8 9
Summary
Summary 1. Basic Pharmacokinetic Profile of Propafenone 1.1 Absorption 1.2 Distribution 1.3 Metabolism and Elimination 2. Electrophysiological Effects of Propafenone 2. 1 In Vitro Effects 2.2 In Vivo Effects 3. Pharmacokinetic-Pharmacodynamic Effects 4. Pharmacokinetics of Propafenone in Disease States 4. 1 Hepatic Dysfunction 4.2 Renal Failure 5. Drug Interactions 5.1 Interaction with Digoxin 5.2 Interaction with Warfarin 5.3 Interaction with Propranolol/Metoprolol 5.4 Interaction with Quinidine 6. Adverse Effects 7. Conclusion
Propafenone is a class IC antiarrhythmic agent which is administered as a racemate of S(+)and R(-)-enantiomers. It is well absorbed and is predominantly bound to ai-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 (j-blocking effects. Both the enantiomers and the 5-0H metabolite have a potency to block sodium channels comparable with that of the parent compound. The S-enantiomer is a more potent (j-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
Clin. Pharmacokinet. 21 (1) 1991
2
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.
1. Basic Pharmacokinetic Profile 0/ Propa/enone 1.1 Absorption
Propafenone is administered as a racemic compound. It can be administered either orally or intravenously; after oral administration, more than 90% of the dose is absorbed (Hege et al. 1984; Hollman et al. 1983) and its peak plasma concentration (Cmax ) is usually reached after about 2h. The bioavailability is dependent on several factors: in general, systemic bioavailability ranges from 5 to 50%, which reflects high presystemic clearance. Coadministration of propafenone with food increases its bioavailability (Axelson et al. 1987) although the mechanism of this phenomenon is uncertain. Also, in the presence of food, Cmax is more rapidly attained. It is interesting that such enhancement of propafenone bioavailability by food could only be demonstrated in subjects with the 'extensive metaboliser' phenotype (see below). The mean increase in area under the concentration-time curve (AUC) was 147% when only extensive metaboliser phenotype subjects were used in the calculation, and 120% when all subject data were incorporated. Propafenone bioavailability is also determined by the dosage form (Hollmann et al. 1983). When administered as a solution, the bioavailability is higher, but it is only about 12% following administration of a 300mg film-coated tablet. Propafenone bioavailability is also dose-dependent, rising as the dose is increased. This is partly due to a decrease in its presystemic clearance (Connolly et al. 1983a; Hollmann et al. 1983). The dose-concentration relationship is not always linear: Hollmann et al. (1983), using single doses of propafenone in healthy volunteers, showed a 6-fold increase in plasma concentration as the oral dose was in-
creased 3-fold. In another study (Connolly et al. 1983a), there was a 10-fold increase in the mean steady state propafenone concentration as the dosage was increased 3-fold (fig. 1). These observations further supported the concept of saturable metabolism for this drug. A more recent study indicates that the nonlinear dose-concentration relationship occurs in subjects with the extensive metaboliser phenotype, suggesting that 5-hydroxylation of propafenone is saturable. In subjects with
1000
~ ..:!. J~ 750
~
(I)
