Genetic polymorphism of CYP2D6 and CYP2C19 in East- and Southern African populations including psychiatric patients

Dandara, Collet; Masimirembwa, Collen; Magimba, Ayoub; Sayi, Jane; Kaaya, Sylvia; Sommers, De K.; Snyman, J. R.; Hasler, Julia A.

doi:10.1007/s002280100282

Cited by 79 publications

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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).…”

mentioning

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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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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“…In linguistically related populations (Bantu) in Eastern and Southern Africa, a low prevalence of people with deficient CYP2D6 activity was found. However, the high frequency of the low-activity CYP2D6*17 allele predicts that the Bantu people have a reduced capacity to metabolize drugs that are CYP2D6 substrates [38]. Many studies of mutant alleles have demonstrated genetic heterogeneity in different black African populations [5].…”

Section: Dosage Predictionmentioning

confidence: 99%

Pharmacogenetics and Drug Therapy in Psychiatry - The Role of the CYP2D6 Polymorphism

Vandel¹,

Talon²,

Haffen³

et al. 2007

CPD

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The importance of pharmacogenetics in medicine is growing with the identification of genetic variability by faster screening methods using automatic sequencers. A particularly interesting finding is that apart from environmental and psychological factors, drug response may be influenced by several biological factors as a result of genetic determinants leading to interindividual variability. Several mutations in genes coding for enzymes of the drug metabolizing system, as well as for neurotransmitter receptors or degrading enzymes and monoamine transport proteins, have been identified and investigated in psychiatry. But, despite the fact that some genetic polymorphisms of enzymes (mainly cytochrome P450 2D6) are well known, the application of pharmacogenetics as a therapeutic tool for improving patient care is rare. This review has three parts. In the first an overview is given of CYP450 characteristics and the genetic polymorphisms of interest to psychiatry. In the second the clinical implications of the CYP2D6 polymorphism are reviewed and in the third part other aspects on pharmacogenetic research in psychiatry are discussed. The aim of our review is to promote the application of pharmacogenetics in everyday clinical practice.

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“…This allele results in the production of an unstable enzyme, caused by a double amino acid substitution ( Table 1) [23]. The most commonly found allele in the African population is CYP2D6*17 [24]. It is also associated with an IM phenotype, resulting in reduced catalytic activity caused by a triple amino acid substitution ( Table 1) [23].…”

Section: Genetic Aspects Of Cyp2d6mentioning

confidence: 99%

Pharmacogenetics of Cytochrome P450 2D6: A Translational Medicine Perspective

Shah

Breslin²,

Wittayanarakul³

et al. 2010

TOPROCJ

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Abstract:With rapid scientific advances in the postgenomic era, pharmacogenomics has developed into an important area of translational medicine research. Pharmacogenetics studies the variability in drug response between different patient genotypes. By using patient genomic information, this bench-to-bedside research approach aims to develop more effective targeting of drug therapy in clinical practice. This will potentially reduce the risk of adverse drug reactions and avoid treatment failure. One of the important areas of pharmacogenetic variability is in drug metabolism via the cytochrome P450 (CYP) enzyme system. Cytochrome P450 2D6 (CYP2D6) metabolises up to 30% of commonly used drugs but this enzyme displays extensive genetic polymorphism. The approval of CYP2D6 genotype testing by the FDA in 2005 has put this enzyme at the cutting-edge of research into personalised medicine. The effects of CYP2D6 genetic polymorphism on tamoxifen metabolism and clinical outcomes in breast cancer patients is currently an important area of translational research. This review article covers recent progress in CYP2D6 pharmacogenomics and its applications to translational medicine.

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Genetic polymorphism of CYP2D6 and CYP2C19 in East- and Southern African populations including psychiatric patients

Cited by 79 publications

References 0 publications

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

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

Pharmacogenetics and Drug Therapy in Psychiatry - The Role of the CYP2D6 Polymorphism

Pharmacogenetics of Cytochrome P450 2D6: A Translational Medicine Perspective

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