Drug interaction between propafenone and metoprolol.

Wagner, F.; Kalusche, D.; Trenk, Dietmar; Jähnchen, E.; Roskamm, H.

doi:10.1111/j.1365-2125.1987.tb03164.x

Cited by 64 publications

(20 citation statements)

References 8 publications

(5 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A marked increase in plasma AUC after pregnancy has been reported for metoprolol (Hogstedt et al, 1985), a drug which shares the same polymorphic metabolic pathway as propafenone (Wagner et al, 1987) and to a lesser extent for other drugs that are oxidized (Dam et al, 1979). Thus the metabolism of propafenone also appears to increase during pregnancy.…”

mentioning

confidence: 97%

Transfer of propafenone and 5‐OH‐propafenone to foetal plasma and maternal milk [letter]

Libardoni

Piovan

Busato

et al. 1991

Brit J Clinical Pharma

View full text Add to dashboard Cite

mentioning

confidence: 97%

Transfer of propafenone and 5‐OH‐propafenone to foetal plasma and maternal milk [letter]

Libardoni

Piovan

Busato

et al. 1991

Brit J Clinical Pharma

View full text Add to dashboard Cite

“…Similarly, propafenone has been shown to produce 2-to 5-fold increases in steady-state plasma metoprolol concentrations in unphenotyped patients (Wagner et al 1987a). However, the pharmacodynamic and clinical consequences of these findings have not been investigated.…”

Section: Cardiovascular Drugsmentioning

confidence: 97%

“…The inhibitory effect of propafenone, which is metabolised by CYP2D6, is not restricted to this P450 isozyme. Propafenone inhibits the CYP2D6-catalysed metabolism of metoprolol, presumably by a competitive process, causing 2-to 5-fold increases in steady-state drug concentrations (Wagner et al 1987a). The toxicological consequences of this interaction were not systematicidly evaluated but important adverse effects were reported by 2 patients during the combined drug phase of this study.…”

Section: Cardiovascular Drugsmentioning

confidence: 98%

Genetically Determined Adverse Drug Reactions Involving Metabolism

Lennard

1993

Drug Safety

View full text Add to dashboard Cite

Genetic factors represent an important source of interindividual variation in drug response. Relatively few adverse drug effects with a pharmacodynamic basis are known, and most of the well characterised inherited traits take the form of genetic polymorphisms of drug metabolism. Monogenic control of N-acetylation, S-methylation and cytochrome P450-catalysed oxidation of drugs can have important clinical consequences. Individuals who inherit an impaired ability to perform one or more of these reactions may be at an increased risk of concentration-related toxicity. There is a strong case for phenotyping before starting treatment with a small number of drugs that are polymorphically N-acetylated or S-methylated. However, the issue of clinical significance is perhaps most relevant for the debrisoquine oxidation polymorphism, which is mediated by cytochrome CYP2D6 and which determines the pharmacokinetics of many commonly used drugs. Phenotypic poor metabolisers of debrisoquine (8% of Caucasian populations) taking standard doses of some tricyclic antidepressants, neuroleptics or antiarrhythmic drugs may be particularly prone to adverse reactions. Similarly, clinically relevant drug interactions between these drugs and other substrates of cytochrome CYP2D6 may occur in the majority of the population who are extensive metabolisers. However, it is clear that in the majority of cases there is a need for controlled prospective studies to determine clinical significance. Accordingly, routine debrisoquine phenotyping or genotyping before beginning drug treatment is difficult to justify at present, although it may be helpful in individual cases. When prescribing drugs whose metabolism is polymorphic alone or in combination, careful titration of the dose in both phenotypic groups is prudent. In some cases it will be preferable to use alternative therapy to avoid the risk of adverse drug reactions.

show abstract

“…One of these patients was simultaneously taking antiarrhythmic agent propafenone, the second one antidepressive agent sertraline, agents known to inhibit P450 2D6 activity. Two to fi ve-fold increase in the steady-state levels of metoprolol has been described in patients after propafenone was added to the metoprolol therapy even with an occurrence of adverse effects in some patients (25,26). Discontinuation of propafenone therapy switched the patient´s phenotype from PM to EM (26).…”

Section: Discussionmentioning

confidence: 99%

Cytochrome P450 2D6 phenotype and genotype in hypertensive patients on long-term therapy with metoprolol

Perinova¹,

Jurckova²,

Ježíšková³

et al. 2013

BLL

View full text Add to dashboard Cite

Objective:The aim was to compare cytochrome P450 2D6 phenotype and genotype using metoprolol as a probe drug. Further, to investigate the infl uence of P450 2D6 activity on metoprolol pharmacokinetics and pharmacodynamics in patients on metoprolol therapy. Background: Cytochrome P450 2D6 is a highly polymorphic enzyme that contributes to the variability of metoprolol. However, environmental factors also modify drug disposition. Methods: Forty-nine hypertensive patients were enrolled. Serum metoprolol and α-hydroxymetoprolol concentrations, resting heart rate were measured before, 1, 3 and 4 hours post-dose. Results: Signifi cantly higher normalized metoprolol serum concentrations, normalized metoprolol AUC 0-4 and metoprolol oral clearance were observed in patients with lower P450 2D6 metabolic activity. A trend towards a lower resting heart rate before metoprolol intake was also observed in this group of patients. The differences in metoprolol disposition were more expressed when P450 2D6 phenotype instead of genotype was determined. Conclusion: Signifi cant variations exist in metoprolol disposition in hypertensive patients. Both genotyping and phenotyping provides a valuable method in determining the enzymatic activity and in optimising metoprolol therapy (Tab. 3, Fig. 8, Ref. 35 The cytochromes P450 (P450) are the superfamily of hemecontaining monooxygenases playing an important role in the biotransformation of both endogenous and exogenous compounds (1). Most human P450s that participate in drug metabolism show a considerable interindividual variability in most humans in both levels of expression and catalytic activity. This variability is due to both environmental and genetic factors (2). P450 2D6 (known as debrisoquine/sparteine hydroxylase) is a highly polymorphic enzyme (3). To date, more than 100 different P450 2D6 allelic variants and sub-variants have been defi ned (4). In general, genotypes may be differentiated into four subgroups: poor (PM), intermediate (IM), extensive (EM) and ultrarapid (UM) metabolizers. Subjects with a PM genotype lack any functional allele, whereas EMs have two and UM subjects have more than two functional alleles. Subjects with IM genotype are heterozygous for a specifi c variant allele and/or possess alleles with reduced activity (4). The frequency of individual variants of P450 2D6 shows a marked interethnic difference. In white European populations, the percentage of PM varies from 3.2 % (Finish) to 11.7 % (Germans), but PMs constitute less than 1 % of Asian subjects (6, 7). Beside the genetic variability, environmental factors such as dietary habits (8) or drug interactions may also modify drug disposition (9). In vivo P450 phenotyping has proven to be very successful in predicting the actual enzymatic activity. It is based on administration of an adequate probe drug followed by measurement and calculation of metabolic ratio (MR) of a parent compound to its metabolite mediated by P450 of interest. The MR of P450 2D6 probe drugs shows bimodal or even trimodal d...

show abstract

Drug interaction between propafenone and metoprolol.

Cited by 64 publications

References 8 publications

Transfer of propafenone and 5‐OH‐propafenone to foetal plasma and maternal milk [letter]

Transfer of propafenone and 5‐OH‐propafenone to foetal plasma and maternal milk [letter]

Genetically Determined Adverse Drug Reactions Involving Metabolism

Cytochrome P450 2D6 phenotype and genotype in hypertensive patients on long-term therapy with metoprolol

Contact Info

Product

Resources

About