Debrisoquine oxidative phenotyping and psychiatric drug treatment

Derenne, F; Joanne, Christiane; Vandel, S; Bertschy, Gilles; Volmat, R; Bechtel, P

doi:10.1007/bf00561023

Cited by 28 publications

(12 citation statements)

References 26 publications

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“…This result is in agreement with those of our previous studies (Derenne et al, 1989;Perault et al, 1991;Vandel et al, 1999). It was probably due to the saturation of the metabolic pathways by the antidepressants.…”

Section: Phenotyping Datasupporting

confidence: 95%

Clomipramine, fluoxetine and CYP2D6 metabolic capacity in depressed patients

Vandel

Haffen

Nezelof

et al. 2004

Human Psychopharmacology

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Cytochrome P450-2D6 may be involved in the metabolism of many drugs such as psychotropic drugs and its genetic polymorphism is responsible for inter-individual differences in the therapeutic effect and toxicity of these drugs. Moreover with the same genetic basis, CYP2D6 metabolic capacity variations are observed. Different factors of variation may be involved, among them the prescribed drugs. The aim of this study was to compare the influence of two types of antidepressants, tricyclic (clomipramine) and serotonergic specific recapture inhibitor (SSRI) (fluoxetine), on the CYP2D6 metabolic capacity of depressed inpatients. The CYP2D6 phenotype (dextromethorphan test) was determined in 56 genotyped (PCR-SSCP) depressed caucasian inpatients with a heterozygous genotype. Forty-five subjects were treated with clomipramine and eleven received fluoxetine. The dextromethorphan metabolic ratio (MR) median was significantly higher in the fluoxetine group (0.255) than in the clomipramine group (0.083, p < 0.014). In this study, fluoxetine involved a greater decrease of CYP2D6 metabolic capacity than clomipramine. Clinical implications and the possible connection between a decreased CYP2D6 activity and adverse drug effects were discussed. Caution should be taken when drugs with a low therapeutic index must be coprescribed in such patients.

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Section: Phenotyping Datasupporting

confidence: 95%

Clomipramine, fluoxetine and CYP2D6 metabolic capacity in depressed patients

Vandel

Haffen

Nezelof

et al. 2004

Human Psychopharmacology

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“…The remaining variability may result from other factors interacting with antidepressant metabolism; e.g., enzymatic induction by smoking (Perel et al, 1978) or alcohol (Choisy et al, 1986). In the authors' work, factors such as drug-drug interaction (Derenne et al, 1988) and associated kidney or liver disease (Sandozet al, 1983;Sandozet al, 1984) were excluded, while the dose prediction test lessened the importance of the genetically determined polymorphism of drug metabolism.…”

Section: Discussionmentioning

confidence: 99%

Desipramine Dose Prediction Based on 24-Hour Single-Dose Levels: Feasibility and Validity

Bertschy¹,

Vandel²,

Vandel³

et al. 1989

Pharmacopsychiatry

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The authors present a prospective study of a rapid desipramine dose adjustment on the basis of a 24-hour plasma concentration after a single 150 mg dose. For this, they use a prediction table constructed from data in the literature showing strong correlation between steady-state plasma levels and 24-hour single-dose levels. Despite the fact that desipramine action is not always linear, the method appears to be feasible and valid. In an attempt to reach a 150 ng/ml level, the authors obtained steady-state levels ranging from 85 to 317 ng/ml, with 14 of the 19 patients in the range between 125 and 250 ng/ml. Moreover, 11 of the 19 patients received a daily dose of 250 mg or more desipramine from the third day of treatment onward; in ten of these cases, this dose had been adapted.

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“…Several studies have shown that antipsychotic drugs, particularly the phenothiazines, are potent inhibitors of debrisoquine or sparteine oxidation (Derenne et al 1989;Gram et al 1989;Spina et al 1991;Syvalahti et al 1986). For example, in a group of patients with schizophrenia receiving monotherapy with antipsychotic drugs, the distribution of the debrisoquine to 4-hydroxy-debrisoQuine ratio, an inverse index of CYP2D6 activity, was found to show a large shift to higher values compared with that of a healthy volunteer group ( fig.…”

Section: Antidepressants and Antipsychoticsmentioning

confidence: 97%

Genetically Determined Adverse Drug Reactions Involving Metabolism

Lennard

1993

Drug Safety

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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.

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Debrisoquine oxidative phenotyping and psychiatric drug treatment

Cited by 28 publications

References 26 publications

Clomipramine, fluoxetine and CYP2D6 metabolic capacity in depressed patients

Clomipramine, fluoxetine and CYP2D6 metabolic capacity in depressed patients

Desipramine Dose Prediction Based on 24-Hour Single-Dose Levels: Feasibility and Validity

Genetically Determined Adverse Drug Reactions Involving Metabolism

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