Phenotypic debrisoquine 4‐hydroxylase activity among extensive metabolizers is unrelated to genotype as determined by the Xba‐I restriction fragment length polymorphism.

Turgeon, Jacques; We, Evans; Relling, M V; Wilkinson, G. R.; Roden, DM

doi:10.1111/j.1365-2125.1991.tb03900.x

Cited by 6 publications

(2 citation statements)

References 26 publications

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“…It has also been shown previously that, among genotypic extensive metabolizers, phenotypic CYP2D6 activity can vary markedly. 21 Indeed, this was shown in this study with a very wide range of plasma propafenone in the group of extensive metabolizers.…”

Section: Verification Of Randomization and Compliancesupporting

confidence: 65%

Quinidine-enhanced β-blockade during treatment with propafenone in extensive metabolizer human subjects

Mörike

Roden

1994

Clin Pharmacol Ther

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Propafenone, a sodium channel blocking antiarrhythmic drug with beta-blocking properties, is metabolized to non-beta-blocking metabolites in part by cytochrome P4502D6. Subtherapeutic doses of quinidine inhibit P4502D6 and increase plasma propafenone in extensive metabolizer subjects, in whom the active enzyme is present. In this study we tested the hypothesis that quinidine would enhance beta-blockade in extensive metabolizers receiving propafenone. Seven extensive and two poor metabolizers received propafenone (225 mg orally every 8 hours) plus quinidine sulfate (60 mg orally every 8 hours) or propafenone plus placebo for 7 days in a randomized, double-blind, crossover fashion. In extensive metabolizers, the coadministration of quinidine significantly increased the extent of propafenone-induced beta-blockade, assessed by a decrease in exercise heart rate and by sensitivity to isoproterenol. We conclude that low-dose quinidine enhances propafenone-induced beta-blockade in extensive metabolizers. Thus the polymorphic patterns of drug metabolism can result in clinically significant drug interactions on a genetic basis.

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Section: Verification Of Randomization and Compliancesupporting

confidence: 65%

Quinidine-enhanced β-blockade during treatment with propafenone in extensive metabolizer human subjects

Mörike

Roden

1994

Clin Pharmacol Ther

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“…This is relevant and important, especially in epidemiological genotypic screening of individuals to predict the metabolic phenotype. They also explain some of the reported discrepancies in genotype-phenotype correlation (Broly et al, 1991;Daly et al, 1990;Turgeon et al, 1991). However, it is intriguing to find that the presence of an additional gene coincides with the occurence of the D6-B mutation in the XbaI 44kbD6-B allele.…”

Section: Discussionmentioning

confidence: 84%

Molecular heterogeneity of the XbaI defined 44kb allele of the CYP2D locus within the Caucasian population.

Mura

Gérard

Vincent‐Viry

et al. 1993

Brit J Clinical Pharma

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1. Cytochrome P450 debrisoquine (CYP2D6) activity is polymorphic and under genetic control. Most Caucasians are extensive metabolizers, but 5%‐10% are poor metabolizers. 2. Restriction fragment length polymorphism analysis of the CYP2D6 locus identifies a 29kb XbaI fragment, either normal (D6‐wt) or mutated, and three mutated XbaI alleles (44kb, 11.5kb and 16 + 9kb). The 44kb allele was initially considered as a poor metabolizer allele owing to a D6‐B mutation, but cases of 44kb allele not carrying the D6‐B, and therefore potentially functional, have been found. The degree of molecular heterogeneity of this allele was investigated by phenotype and genotype analysis of families. 3. Thirty‐one French Caucasian families, representing 117 individuals, possessing at least one 44kb allele in each family were selected. Phenotypes were determined using dextromethorphan, and the XbaI, NcoI and BamH1 RFLPs of 42 independent chromosomes were analyzed. 4. 80% of the XbaI 44kb alleles carried the CYP2D6‐B mutation and had an additional NcoI fragment (12.5kb or 4.8kb). The remaining 20% did not carry the CYP2D6‐B or A mutations and had no extra NcoI fragment. 5. Information on three families demonstrated that 44kb alleles not carrying the CYP2D6‐B mutation were associated with the extensive metabolizer phenotype. 6. We conclude that a substantial percentage of XbaI 44kb alleles is associated with a functional CYP2D gene, and therefore, that the XbaI 44kb allele is not consistently a poor metaboliser allele.

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Determination of dextromethorphan metabolic phenotype by salivary analysis with a reference to genotype in Chinese patients receiving renal hemodialysis*

Hou

Chen

et al. 1996

Clin Pharmacol Ther

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Determination of dextromethorphan metabolic ratios in saliva is feasible in patients with renal failure requiring hemodialysis. All subjects in this study appeared to be "extensive metabolizer" phenotype for CYP2D6, and no poor metabolizer was identified. From the results with quinidine pretreatment, a metabolic ratio of 33 is suggested to be a tentative antimode for identification of poor metabolizers in patients with renal failure.

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Phenotypic debrisoquine 4‐hydroxylase activity among extensive metabolizers is unrelated to genotype as determined by the Xba‐I restriction fragment length polymorphism.

Cited by 6 publications

References 26 publications

Quinidine-enhanced β-blockade during treatment with propafenone in extensive metabolizer human subjects

Quinidine-enhanced β-blockade during treatment with propafenone in extensive metabolizer human subjects

Molecular heterogeneity of the XbaI defined 44kb allele of the CYP2D locus within the Caucasian population.

Determination of dextromethorphan metabolic phenotype by salivary analysis with a reference to genotype in Chinese patients receiving renal hemodialysis*

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