Pharmacokinetic and pharmacodynamic evaluation of propafenone in patients with ventricular arrhythmia

Zoble, Robert G.; Kirsten, Edward B.; Brewington, Janise; Group, The Propafenone Research

doi:10.1038/clpt.1989.69

Cited by 20 publications

(5 citation statements)

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“…In clinical situations, it has been shown that a plasma PPF concentration of higher than 1.5 mg/mL (4.39 mM) is necessary for the premature ventricular beats, couplet beats, and ventricular tachycardia beats to be suppressed by more than 90% [24]. As the drug concentrations around the enzymes in the liver are higher than the plasma concentrations, racemic PPF and individual PPF enantiomers at a concentration of 10 mM for each enantiomer were incubated for 30 min with each enzyme.…”

Section: Discussionmentioning

confidence: 99%

“…CYP2A6, CYP2B6, CYP2C9, and CYP2C19 did not produce any detectable 5OH-PPF and NOR-PPF. The ability of the cDNA-expressed human CYPs to form NOR-PPF with a 30 min incubation at a clinically relevant concentration (10 mM of each enantiomer [24,25]) and having 12.5 pmol CYP enzyme is further shown with the formation rate data presented in Table 1. The preference of each pathway for catalyzing PPF dealkylation in presence of racemic PPF and of individual PPF enantiomers is thereby documented.…”

Section: Ppf Hydroxylation and N-dealkylation With Cdna-expressed Hummentioning

confidence: 99%

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

Afshar

Thormann

2006

Electrophoresis

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An enantioselective CE method was used to identify the ability of CYP450 enzymes and their stereoselectivity in catalyzing the transformation of propafenone (PPF) to 5-hydroxy-propafenone (5OH-PPF) and N-despropyl-propafenone (NOR-PPF). Using in vitro incubations with single CYP450 enzymes (SUPERSOMES), 5OH-PPF is shown to be selectively produced by CYP2D6 and N-dealkylation is demonstrated to be mediated by CYP2D6, CYP3A4, CYP1A2, and CYP1A1. For the elucidation of kinetic aspects of the metabolism with CYP2D6 and CYP3A4, incubations with individual PPF enantiomers and racemic PPF were investigated. With the exception of the dealkylation in presence of R-PPF only, which can be described by the Michaelis-Menten model, all CYP2D6-induced reactions were found to follow autoactivation kinetics. For CYP3A4, all NOR-PPF enantiomer formation rates as function of PPF enantiomer concentration were determined to follow substrate inhibition kinetics. The formation of NOR-PPF by the different enzymes is stereoselective and is reduced significantly when racemic PPF is incubated. Clearance values obtained for CYP3A4 dealkylation are stereoselective whereas those of CYP2D6 hydroxylation are not. This paper reports the first investigation of the PPF hydroxylation and dealkylation kinetics by the CYP2D6 enzyme and represents the first report in which enantioselective CE data provide the complete in vitro kinetics of metabolic steps of a drug.

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Section: Discussionmentioning

confidence: 99%

Section: Ppf Hydroxylation and N-dealkylation With Cdna-expressed Hummentioning

confidence: 99%

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

Afshar

Thormann

2006

Electrophoresis

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“…With oral administration, Cmax usually occurs about 2 to 3h after administration (Blanke et al 1979;Connolly et al 1983a;Giani et al 1988;Hollmann et al 1983;Keller et al 1978;Seipel & Breithardt 1980;Siddoway et al 1987;Zoble et al 1989). The volume of the central compartment is about 0.7 to 1.1 L/kg and the steady-state volume of distribution is about 1.9 to 3 L/kg Seipel & Breithardt 1980).…”

Section: Tissue Distribution and Disposition Kineticsmentioning

confidence: 95%

Clinical Pharmacokinetics of Propafenone

Hii

Duff

Burgess

1991

Clinical Pharmacokinetics

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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.

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“…For effective suppression of ventricular arrhythmias, propafenone concentrations of 0.5-1 .Opg/ml are required. This concentration can be achieved in PMs by daily dose of 450mg of propafenone while the EMS require 900mg on average (Zoble et al 1989). Similarly, PMs are susceptible to toxic effects of nortriptyline at the recommended doses, while ultrafast EMS require much higher than recommended doses for therapeutic efficacy (Bertilsson et al 1981(Bertilsson et al , 1985(Bertilsson et al , 1993.…”

Section: Other Drugsmentioning

confidence: 96%

Clinical pharmacokinetics: current requirements and future perspectives from a regulatory point of view

Rr¹

1993

Xenobiotica

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1. There is an increasing appreciation of the relevance of pharmacokinetics of drugs during evaluation of their safety for human clinical use. Regulatory requirements for clinical pharmacokinetic data have progressively evolved to emphasize and address these safety implications. 2. Historically the dose schedules usually recommended have been too high, often with serious consequences. Therefore, the need to establish reliable dose response (both therapeutic and toxic) relationships must be an important objective. 3. Concurrent developments in our understanding of the pharmacological effects (therapeutic or toxic) of metabolites, the interethnic and interindividual differences in drug responses and the toxicological aspects of drug chirality now provide compelling reasons for the roles of bioactivation, pharmacogenetics and stereochemical factors to be addressed in pharmacokinetic studies during the clinical development of drugs. 4. Apart from the traditional pharmacokinetic studies following single and multiple doses in healthy volunteers, patients and special subgroups, reliable dose-response curves for therapeutic and toxic effects must be established in well-designed controlled studies using a wide range of doses. Often, doses lower than those recommended have a much improved risk/benefit ratio. 5. Secondary pharmacology of the drug and its active metabolites must be defined for assessment of safety (adverse reactions and pharmacokinetic and pharmacodynamic drug-drug interactions) in high dose/concentration situations. 6. The enzyme systems responsible for the metabolism of a drug must be identified followed by rational investigations of drug-drug and drug-disease interactions both from the efficacy and safety viewpoints. Factors responsible for alterations in the functional expression of this enzyme system must be identified and the safety and efficacy implications of these findings at interethnic, inter- and intraindividual levels must be fully explored during all phases of the clinical development of the drug. This should lead to carefully designed patient subgroup-specific dose schedules which maximize the risk/benefit ratio for all patients. 7. Drugs operate in a chiral environment and, not surprisingly, enantiomers of a drug differ significantly in their pharmacokinetics and pharmacodynamics. The possibility of interactions between enantiomers of a drug and of enantioselective interactions should be examined. These should be thoroughly investigated and the decision to market a racemic mixture or one of its enantiomers must be justified. 8. Analysis of population pharmacokinetics offers an approach by which to examine the roles of various factors which are likely to be clinically relevant for the safe and effective use of drugs.(ABSTRACT TRUNCATED AT 400 WORDS)

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Pharmacokinetic and pharmacodynamic evaluation of propafenone in patients with ventricular arrhythmia

Cited by 20 publications

References 0 publications

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

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

Clinical Pharmacokinetics of Propafenone

Clinical pharmacokinetics: current requirements and future perspectives from a regulatory point of view

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