Pharmacogenetics of cytochrome P450 and its applications in drug therapy: the past, present and future

Ingelman‐Sundberg, Magnus

doi:10.1016/j.tips.2004.02.007

Cited by 570 publications

(369 citation statements)

References 72 publications

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“…It has b een estimated that pretreatment metabolic determination may decrease adverse reactions by 10-20% and improve efficacy by 10-15% (probably by increasing treatment adherence). 82 Aside from genetic determinants, metabolic rates can also be influenced by concomitant treatment and the inhibitory or inductive action of certain drugs ( Table 2). Concomitant treatment with drug substrates for the same enzyme may lead to saturation and toxic metabolite accumulation.…”

Section: Pharmacokinetic Factorsmentioning

confidence: 99%

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

2007

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The last decade of research into the pharmacogenetics of antipsychotics has seen the development of genetic tests to determine the patients' metabolic status and the first attempts at personalization of antipsychotic treatment. The most significant results are the association between drug metabolic polymorphisms, mainly in cytochrome P450 genes, with variations in drug metabolic rates and side effects. Patients with genetically determined CYP2D6 poor metabolizer (PMs) status may require lower doses of antipsychotic. Alternatively, CYP2D6 ultrarapid matabolizers (UMs) will need increased drug dosage to obtain therapeutic response. Additionally, polymorphisms in dopamine and serotonin receptor genes are repeatedly found associated with response phenotypes, probably reflecting the strong affinities that most antipsychotics display for these receptors. In particular, there is important evidence suggesting association between dopamine 2 receptor (D2) polymorphisms (Taq I and À141-C Ins/Del) and a dopamine 3 receptor (D3) polymorphism (Ser9Gly) with antipsychotic response and drug-induced tardive dyskinesia. Additionally, there is accumulating evidence indicating the influence of a 5-HT2C polymorphism (À759ÀT/C) in antipsychotic-induced weight gain. Application of this knowledge to clinical practice is slowly gathering pace, with pretreatment determination of individual's drug metabolic rates, via CYP genotyping, leading the field. Genetic determination of patients' metabolic status is expected to bring clinical benefits by helping to adjust therapeutic doses and reduce adverse reactions. Genetic tests for the pretreatment prediction of antipsychotic response, although still in its infancy, have obvious implications for the selection and improvement of antipsychotic treatment. These developments can be considered as successes, but the objectives of bringing pharmacogenetic and pharmacogenomic research in psychiatric clinical practice are far from being realized. Further development of genetic tests is required before the concept of tailored treatment can be applied to psychopharmatherapy. This review aims to summarize the key findings from the last decade of research in the field. Current knowledge on genetic prediction of drug metabolic status, general response and drug-induced side effects will be reviewed and future pharmacogenomic and epigenetic research will be discussed.

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Section: Pharmacokinetic Factorsmentioning

confidence: 99%

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

2007

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“…Consequently, each individual has its own CYP450 metabolic profile. As it is estimated that the major CYP450 enzymes are involved in 70-80 % of phase I reactions metabolizing clinically used drugs [4], variability in enzyme activity may result in variability in bioavailable drug levels and, consequently, variable response to drug therapy. When the parent drug is pharmacologically active, impaired enzyme function may increase the risk of developing adverse drug reactions (ADRs).…”

Section: Introductionmentioning

confidence: 99%

“…Some CYP450 enzymes, in particular CYP2D6, CYP2C19 and CYP2C9, are encoded by highly polymorphic genes and distinct subpopulations can be identified based on the genetic signature [4,7,8]. For many drugs metabolized by these enzymes, clinical outcome could be correlated with a certain genotype and genotyping a patient has proven to be a reliable strategy to assess the metabolic phenotype [3,6,8].…”

Section: Introductionmentioning

confidence: 99%

Alternative Sampling Strategies for Cytochrome P450 Phenotyping

2015

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Interindividual variability in the expression and function of drug metabolizing cytochrome P (CYP) 450 enzymes, determined by a combination of genetic, non-genetic and environmental parameters, is a major source of variable drug response. Phenotyping by administration of a selective enzyme substrate, followed by the determination of a specific phenotyping metric, is an appropriate approach to assess the in vivo activity of CYP450 enzymes, as it takes into account all influencing factors. A phenotyping protocol should be as simple and convenient as possible. Typically, phenotyping metrics are determined in traditional matrices, such as blood, plasma or urine. Several sampling strategies have been proposed as an alternative for these traditional sampling techniques.In this review, we provide a comprehensive overview of available methods using dried blood spots, hair, oral fluid, exhaled breath and sweat for in vivo CYP450 phenotyping. We discuss the relation between phenotyping metrics measured in these samples and those in conventional matrices, along with the advantages and limitations of the alternative sampling techniques. Reliable phenotyping procedures for several clinically relevant CYP450 enzymes, including CYP1A2, CYP2C19 and CYP2D6, are currently available for oral fluid, breath or dried blood spots, while additional studies are needed for other CYP450 isoforms, such as CYP3A4. The role of hair analysis for this purpose remains to be established. Being non-or minimally invasive, these sampling strategies provide convenient and patient-friendly alternatives for classical phenotyping procedures, which may contribute to the implementation of CYP450 phenotyping in clinical practice. 4 Key Points Phenotyping by administration of a selective probe drug, followed by determination of a specific phenotyping metric, allows to assess the in vivo enzyme activity of CYP450 enzymes, taking into account genetic, non-genetic and environmental influencing factors. In addition to classical sampling techniques, such as blood or urine collection, reliable phenotyping procedures for several clinically relevant CYP450 enzymes are currently available for oral fluid, breath and dried blood spots.

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“…For metabolism, interindividual variation in the phase-I metabolising enzymes of the cytochrome P 450 (CYP) system is a widely recognized source of between-patient differences regarding drug therapy response [9] and plays an important role in drug safety.…”

Section: Introductionmentioning

confidence: 99%

“…The CYP2D6 and CYP3A enzymes together are responsible for about 60-75% of phase-I reactions undergone by all drugs metabolised through the CYP system and show extensive interindividual variation [9]. Also, these enzymes play an important role in many drug interactions.…”

Section: Introductionmentioning

confidence: 99%

Changes in the defined daily dose; CYP2D6/CYP3A metabolism as an indicator for dose-setting problems

Stolk

Heerdink

Leufkens

2005

Eur J Clin Pharmacol

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Objective: Interindividual variability is common at all stages of drug absorption, distribution, pharmacodynamics, metabolism and elimination. In this study, we focused on two enzymes involved in phase-I drug metabolism as markers of pharmacological variability: the CYP3A and CYP2D6 subsystems of cytochrome P 450 . The main aim of our study was to determine whether substrate drugs for CYP2D6 and/or CYP3A enzymes, showing high interindividual matabolic variability, are more prone to postmarketing adjustments of defined daily dose (DDD). Methods: A case-control design was used. We identified all DDD changes between 1982 and May 2004 through the website of the WHO Collaborating Centre for Drug Statistics Methodology. Cases were drugs with a DDD change and controls were other drugs with unchanged DDDs. Information about metabolism pathway, introduction year, literature exposure and administration route was retrieved. Results: We included 88 cases and 176 controls. Of the 88 cases, 51 were dosage decreases (58.0%). Overall, DDD changes were not associated with CYP2D6/ CYP3A metabolism (OR 1.92;. However, DDD decreases were associated with CYP2D6/CYP3A metabolism (OR 3.21; 95%CI 1.25-8.26). Adjusting for introduction year weakened this effect (OR 2.78; 95%CI 0.98-7.90). Conclusion: Our study indicates that CYP2D6 and CYP3A substrates are more likely to require a DDD decrease after granting of market authorisation. However, this effect was diminished by adjusting for period of introduction. The implication of this finding is that variability indicators, as is demonstrated in this study for CYP2D6/CYP3A metabolism, can exert their influence on a wide variety of drug measures, such as the DDD.

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Pharmacogenetics of cytochrome P450 and its applications in drug therapy: the past, present and future

Cited by 570 publications

References 72 publications

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

Alternative Sampling Strategies for Cytochrome P450 Phenotyping

Changes in the defined daily dose; CYP2D6/CYP3A metabolism as an indicator for dose-setting problems

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