Genetically-determined interaction between propafenone and low dose quinidine: role of active metabolites in modulating net drug effect.

@article{FunckBrentano1989GeneticallydeterminedIB,
  title={Genetically-determined interaction between propafenone and low dose quinidine: role of active metabolites in modulating net drug effect.},
  author={C. Funck-Brentano and H. Kroemer and H. Pavlou and R. Woosley and D. Roden},
  journal={British journal of clinical pharmacology},
  year={1989},
  volume={27 4},
  pages={
          435-44
        }
}
1. Quinidine is a potent inhibitor of the genetically-determined debrisoquine 4-hydroxylation. Oxidation reactions of several other drugs, including the 5-hydroxylation of the new antiarrhythmic drug propafenone, depend on the isozyme responsible for debrisoquine 4-hydroxylation. 2. The effect of quinidine on the debrisoquine phenotype-dependent 5-hydroxylation and the pharmacological activity of propafenone was studied in seven 'extensive' metabolizers and two 'poor' metabolizers of the drug… Expand
The role of genetically determined polymorphic drug metabolism in the beta-blockade produced by propafenone.
TLDR
The degree of beta-blockade during propafenone therapy reflects genetically determined variations in the metabolism of the parent drug, which is necessary for beta-blocking action, and that this action is considerably enhanced in patients with deficient 5-hydroxylation of propAFenone. Expand
Stereoselective genetically-determined interaction between chronic flecainide and quinidine in patients with arrhythmias.
TLDR
The effects of adding low dose quinidine, a potent inhibitor of P450IID6, to chronic flecainide therapy in patients with arrhythmias were evaluated and it was found that in extensive metabolizer patients receiving chronic fle cainide, increased plasma concentrations will develop if P450 IID6 is inhibited. Expand
Effect of selective serotonin reuptake inhibitors on the oxidative metabolism of propafenone: in vitro studies using human liver microsomes.
TLDR
In vitro data suggest that an in vivo interaction between propafenone and the SSRIs, fluoxetine and parxetine, can be expected, which can lead to clinically relevant beta-blockade and an increased risk of side effects in the central nervous system. Expand
Influence of amiodarone on genetically determined drug metabolism in humans
TLDR
It is suggested that amiodarone decreases the activity of CYP2D6 and may impair the elimination of drugs whose clearance depends on this cytochrome in extensive metabo‐lizers of dextromethorphan. Expand
The pharmacokinetic and pharmacodynamic interaction between propafenone and lidocaine
TLDR
The ability of propafenone to inhibit metabolic pathways exclusive of the CYP2D6 isozyme may be limited and potentiation of disturbing central nervous system adverse effects may occur during combination therapy of propAFenone and lidocaine. Expand
Effects of propafenone and its main metabolite, 5-hydroxypropafenone, on HERG channels.
TLDR
It is indicated that propafenone and its main active metabolite, 5-hydroxypropafenones, block HERG channels to a similar extent by binding predominantly to the open state of the channel. Expand
Clinical Pharmacokinetics of Propafenone
TLDR
The drug should be used with caution in patients with serious structural heart disease, as it may cause or aggravate life-threatening arrhythmias and increases the plasma concentrations of digoxin, warfarin, metoprolol and propranolol as well as enhancing their respective pharmacodynamic effects. Expand
Induction of polymorphic 4'-hydroxylation of S-mephenytoin by rifampicin.
TLDR
It appears that the activity of the enzyme (P-450 MP) mediating the genetically determined 4'-hydroxylation of S-mephenytoin can be significantly modulated by enzyme inducing agents such as rifampicin and possibly environmental agents with a similar ability. Expand
Combined Administration of Quinidine and Propafenone for Atrial Fibrillation: The CAQ‐PAF Study
TLDR
Chronic inhibition of CYP2D6 is achievable with low‐dose quinidine in humans and increased plasma levels of propafenone may be highly beneficial to prevent recurrence of atrial fibrillation. Expand
Characterisation of (R/S)-propafenone and its metabolites as substrates and inhibitors of P-glycoprotein
TLDR
5-hydroxypropafenone is translocated by human P-glycoprotein across cell monolayers and therefore contribute to the digoxin–propafanone interaction observed in humans. Expand
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 31 REFERENCES
Quinidine and the identification of drugs whose elimination is impaired in subjects classified as poor metabolizers of debrisoquine.
TLDR
The effects of quinidine at a dose of only 50 mg, on the metabolism of a new drug in EM subjects may prove a useful method of assessing the contribution of the debrisoquine 4-hydroxylase isozyme to the elimination of the drug tested. Expand
Polymorphism of propafenone metabolism and disposition in man: clinical and pharmacokinetic consequences.
TLDR
It is concluded that propafenone is metabolized via the same cytochrome P-450 responsible for debrisoquine's 4-hydroxylation, and that its pharmacokinetics and concentration-response relationships and the incidence of central nervous system side effects are different in patients of different debrisoquines metabolic phenotype. Expand
Potent electrophysiologic effects of the major metabolites of propafenone in canine Purkinje fibers.
TLDR
These metabolites are sufficiently potent that they may explain at least in part the unpredictable concentration-response relationship seen with propafenone. Expand
Characterization of the common genetic defect in humans deficient in debrisoquine metabolism
TLDR
It is shown that poor meta-bolizers have negligible amounts of the cytochrome P450 enzyme P450dbl, providing a molecular explanation for one of man's most commonly defective genes. Expand
Competitive inhibition of sparteine oxidation in human liver by beta-adrenoceptor antagonists and other cardiovascular drugs.
TLDR
In vitro competitive inhibition of sparteine oxidation by a drug indicates that this drug is capable of occupying the same enzymatic site as spartanine and may mean that the competing drug is also metabolized at that site and thereby subject to the same genetic variation as spartein's oxidation. Expand
In vitro characterization of the human cytochrome P‐450 involved in polymorphic oxidation of propafenone
TLDR
5‐hydroxypropafenone is formed by the cytochrome P‐450 isozyme involved in polymorphic bufuralol oxidation, and was a strong competitive inhibitor ofbufuralol l'hydroxylation. Expand
Pharmacological studies on propafenone and its main metabolite 5-hydroxypropafenone.
TLDR
The results show low CNS activity of propafenone which is even lower for the metabolite but which is distinctly higher for lidocaine and - related to the antiarrhythmic potency - for flecainide, too. Expand
Enhanced antiarrhythmic efficacy of propafenone when used in combination with procainamide or quinidine.
TLDR
Propafenone is an effective antiarrhythmic agent when used in combination with type IA antiarrHythmic drugs, and lower doses of propafen one can be utilized effectively than with propafENone alone. Expand
Extensive metabolizers of debrisoquine become poor metabolizers during quinidine treatment.
TLDR
Inhibition of 4-OH-debrisoquine formation was associated with a disproportionate increase in debrisoquine excretion and the phenotype of the patients was altered to PM. Expand
Impaired oxidation of debrisoquine in patients with perhexiline neuropathy.
TLDR
Routine determination of the drug oxidation phenotype might lead to safer use of perhexiline by predicting patients who may be more at risk of developing a neuropathic reaction associated with its long-term use, and points to a genetic susceptibility to developing neuropathy in response to per hexiline. Expand
...
1
2
3
4
...