Drug extrapyramidal side effects. CYP2D6 genotypes and phenotypes

Vandel, Pierre; Haffen, Emmanuel; Vandel, S; Bonin, Bruno; Nezelof, Sylvie; Sechter, D.; Broly, Franck; Bizouard, P.; Daléry, J

doi:10.1007/s002280050689

Cited by 54 publications

(38 citation statements)

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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%

“…Its genetic polymorphism is responsible for inter-individual differences in the therapeutic effect and toxicity of many drugs (Brosen and Gram, 1989;Chen et al, 1996;Spina et al, 1992;Spina et al, 1994;Vandel et al, 1999). Moreover with the same genetic basis, intra-individual CYP2D6 metabolic capacity variations are observed in patients, with possible clinical implications.…”

Section: Introductionmentioning

confidence: 97%

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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%

Section: Introductionmentioning

confidence: 97%

Clomipramine, fluoxetine and CYP2D6 metabolic capacity in depressed patients

Vandel

Haffen

Nezelof

et al. 2004

Human Psychopharmacology

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“…49 induced seizures was reported in relation to CYP2D6 activity 145 and several studies showed a relationship between extrapyramidal side effects of antipsychotic drugs and CYP2D6 polymorphisms. 96,[146][147][148][149][150][151][152][153][154][155][156] However, compared to the large efforts made to evaluate pharmacokinetic differences due to CYP polymorphisms, few prospective studies on benefit of phenotyping or genotyping for therapeutic outcome have been conducted so far. It was estimated from retrospective assessments that patients with psychiatric disorders Table 2.…”

Section: Impact Of Cyp2c9mentioning

confidence: 99%

Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response

et al. 2004

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Genetic factors contribute to the phenotype of drug response. We systematically analyzed all available pharmacogenetic data from Medline databases on the impact that genetic polymorphisms have on positive and adverse reactions to antidepressants and antipsychotics. Additionally, dose adjustments that would compensate for genetically caused differences in blood concentrations were calculated. To study pharmacokinetic effects, data for 36 antidepressants were screened. We found that for 20 of those, data on polymorphic CYP2D6 or CYP2C19 were found and that in 14 drugs such genetic variation would require at least doubling of the dose in extensive metabolizers in comparison to poor metabolizers. Data for 38 antipsychotics were examined: for 13 of those CYP2D6 and CYP2C19 genotype was of relevance. To study the effects of genetic variability on pharmacodynamic pathways, we reviewed 80 clinical studies on polymorphisms in candidate genes, but those did not for the most part reveal significant associations between neurotransmitter receptor and transporter genotypes and therapy response or adverse drug reactions. In addition associations found in one study could not be replicated in other studies. For this reason, it is not yet possible to translate pharmacogenetic parameters fully into therapeutic recommendations. At present, antidepressant and antipsychotic drug responses can best be explained as the combinatorial outcome of complex systems that interact at multiple levels. In spite of these limitations, combinations of polymorphisms in pharmacokinetic and pharmacodynamic pathways of relevance might contribute to identify genotypes associated with best and worst responders and they may also identify susceptibility to adverse drug reactions.

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“…The consequences of polymorphic enzymes on drug metabolism in relation to efficacy and side effects has been the focus of numerous studies (Vandel et al, 1999;Dandara et al, 2001). For instance, individuals lacking the expression of a polymorphic drug-metabolizing enzyme (commonly referred to as "poor metabolizers" or PMs) will have higher drug exposure if those drugs are metabolized by those polymorphic enzymes, which could lead to exaggerated pharmacology or enhanced side effects relative to the intermediate metabolizer and extensive metabolizer (EM) subjects given the same dose (Mahgoub et al, 1977).…”

Section: Introductionmentioning

confidence: 99%

Minimizing Polymorphic Metabolism in Drug Discovery: Evaluation of the Utility of in Vitro Methods for Predicting Pharmacokinetic Consequences Associated with CYP2D6 Metabolism

Gibbs

Hyland²,

Youdim³

2006

Drug Metab Dispos

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ABSTRACT:Minimizing interindividual variability in drug exposure is an important goal for drug discovery. The reliability of the selective CYP2D6 inhibitor quinidine was evaluated in a retrospective analysis using a standardized approach that avoids laboratory-to-laboratory variation. The goal was to evaluate the reliability of in vitro metabolism studies for predicting extensive metabolizer (EM)/poor metabolizer (PM) exposure differences. Using available literature, 18 CYP2D6 substrates were selected for further analysis. In vitro microsomal studies were conducted at 1 M substrate and 0.5 M P450 to monitor substrate depletion. An estimate of the fraction metabolized by CYP2D6 in microsomes was derived from the rate constant determined with and without 1 M quinidine for 11 substrates. Clearance in EM and PM subjects and fractional recovery of metabolites were taken from the literature. A nonlinear relationship between the contribution of CYP2D6 and decreased oral clearance for PMs relative to EMs was evident. For drugs having <60% CYP2D6 involvement in vivo, a modest difference between EM and PM exposure was observed (<2.5-fold). For major CYP2D6 substrates (>60%), more dramatic exposure differences were observed (3.5-to 53-fold). For compounds primarily eliminated by hepatic P450 and with sufficient turnover to be evaluated in vitro, the fraction metabolized by CYP2D6 in vitro compared favorably with the in vivo data. The in vitro estimation of fraction metabolized using quinidine as a specific inhibitor provided an excellent predictive tool. Results from microsomal substrate depletion experiments can be used with confidence to select compounds in drug discovery using a cutoff of >60% metabolism by CYP2D6.Minimizing interindividual variability in drug exposure is an important goal in drug discovery. One major source of interindividual variability in drug exposure involves clearance. The variable expression of drug-metabolizing enzymes can result in profound differences in drug exposure across a patient population. The genetic basis for interindividual variability has been described for numerous drugmetabolizing enzymes. Some common examples of polymorphic drug-metabolizing enzymes include thiopurine methyltransferase, glutathione S-transferase M1-1, CYP2C9, CYP2C19, CYP2D6, CYP3A5, N-acetyltransferase 1, UGT1A1, and flavin monooxygenase 3 (Haining and Yu, 2003).The consequences of polymorphic enzymes on drug metabolism in relation to efficacy and side effects has been the focus of numerous studies (Vandel et al., 1999;Dandara et al., 2001). For instance, individuals lacking the expression of a polymorphic drug-metabolizing enzyme (commonly referred to as "poor metabolizers" or PMs) will have higher drug exposure if those drugs are metabolized by those polymorphic enzymes, which could lead to exaggerated pharmacology or enhanced side effects relative to the intermediate metabolizer and extensive metabolizer (EM) subjects given the same dose (Mahgoub et al., 1977). Alternatively, if a polymorphic enzyme forms a p...

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Drug extrapyramidal side effects. CYP2D6 genotypes and phenotypes

Abstract: CYP2D6-impaired metabolic capacity may be a contributory factor in extrapyramidal drug side effects.

Cited by 54 publications

References 0 publications

Clomipramine, fluoxetine and CYP2D6 metabolic capacity in depressed patients

Clomipramine, fluoxetine and CYP2D6 metabolic capacity in depressed patients

Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response

Minimizing Polymorphic Metabolism in Drug Discovery: Evaluation of the Utility of in Vitro Methods for Predicting Pharmacokinetic Consequences Associated with CYP2D6 Metabolism

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