Article

Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part II

School of Health Sciences, RMIT University, Melbourne, Victoria, Australia.
Clinical Pharmacokinetics (Impact Factor: 5.49). 01/2009; 48(12):761-804. DOI: 10.2165/11318070-000000000-00000
Source: PubMed

ABSTRACT Part I of this article discussed the potential functional importance of genetic mutations and alleles of the human cytochrome P450 2D6 (CYP2D6) gene. The impact of CYP2D6 polymorphisms on the clearance of and response to a series of cardiovascular drugs was addressed. Since CYP2D6 plays a major role in the metabolism of a large number of other drugs, Part II of the article highlights the impact of CYP2D6 polymorphisms on the response to other groups of clinically used drugs. Although clinical studies have observed a gene-dose effect for some tricyclic antidepressants, it is difficult to establish clear relationships of their pharmacokinetics and pharmacodynamic parameters to genetic variations of CYP2D6; therefore, dosage adjustment based on the CYP2D6 phenotype cannot be recommended at present. There is initial evidence for a gene-dose effect on commonly used selective serotonin reuptake inhibitors (SSRIs), but data on the effect of the CYP2D6 genotype/phenotype on the response to SSRIs and their adverse effects are scanty. Therefore, recommendations for dose adjustment of prescribed SSRIs based on the CYP2D6 genotype/phenotype may be premature. A number of clinical studies have indicated that there are significant relationships between the CYP2D6 genotype and steady-state concentrations of perphenazine, zuclopenthixol, risperidone and haloperidol. However, findings on the relationships between the CYP2D6 genotype and parkinsonism or tardive dyskinesia treatment with traditional antipsychotics are conflicting, probably because of small sample size, inclusion of antipsychotics with variable CYP2D6 metabolism, and co-medication. CYP2D6 phenotyping and genotyping appear to be useful in predicting steady-state concentrations of some classical antipsychotic drugs, but their usefulness in predicting clinical effects must be explored. Therapeutic drug monitoring has been strongly recommended for many antipsychotics, including haloperidol, chlorpromazine, fluphenazine, perphenazine, risperidone and thioridazine, which are all metabolized by CYP2D6. It is possible to merge therapeutic drug monitoring and pharmacogenetic testing for CYP2D6 into clinical practice. There is a clear gene-dose effect on the formation of O-demethylated metabolites from multiple opioids, but the clinical significance of this may be minimal, as the analgesic effect is not altered in poor metabolizers (PMs). Genetically caused inactivity of CYP2D6 renders codeine ineffective owing to lack of morphine formation, decreases the efficacy of tramadol owing to reduced formation of the active O-desmethyl-tramadol and reduces the clearance of methadone. Genetically precipitated drug interactions might render a standard opioid dose toxic. Because of the important role of CYP2D6 in tamoxifen metabolism and activation, PMs are likely to exhibit therapeutic failure, and ultrarapid metabolizers (UMs) are likely to experience adverse effects and toxicities. There is a clear gene-concentration effect for the formation of endoxifen and 4-OH-tamoxifen. Tamoxifen-treated cancer patients carrying CYP2D6*4, *5, *10, or *41 associated with significantly decreased formation of antiestrogenic metabolites had significantly more recurrences of breast cancer and shorter relapse-free periods. Many studies have identified the genetic CYP2D6 status as an independent predictor of the outcome of tamoxifen treatment in women with breast cancer, but others have not observed this relationship. Thus, more favourable tamoxifen treatment seems to be feasible through a priori genetic assessment of CYP2D6, and proper dose adjustment may be needed when the CYP2D6 genotype is determined in a patient. Dolasetron, ondansetron and tropisetron, all in part metabolized by CYP2D6, are less effective in UMs than in other patients. Overall, there is a strong gene-concentration relationship only for tropisetron. CYP2D6 genotype screening prior to antiemetic treatment may allow for modification of antiemetic dosing. An alternative is to use a serotonin agent that is metabolized independently of CYP2D6, such as granisetron, which would obviate the need for genotyping and may lead to an improved drug response. To date, the functional impact of most CYP2D6 alleles has not been systematically assessed for most clinically important drugs that are mainly metabolized by CYP2D6, though some initial evidence has been identified for a very limited number of drugs. The majority of reported in vivo pharmacogenetic data on CYP2D6 are from single-dose and steady-state pharmacokinetic studies of a small number of drugs. Pharmacodynamic data on CYP2D6 polymorphisms are scanty for most drug studies. Given that genotype testing for CYP2D6 is not routinely performed in clinical practice and there is uncertainty regarding genotype-phenotype, gene-concentration and gene-dose relationships, further prospective studies on the clinical impact of CYP2D6-dependent metabolism of drugs are warranted in large cohorts.

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    • "Several CYP450 isoforms are involved in the metabolism of this drug. Among them, CYP3A4 was identified as the major isoenzyme associated with the formation of 2-and 12-hydroxynevirapine, whereas CYP2B6 was reported to be the predominant isoenzyme that originates 3-and 8-hydroxynevirapine. [92] [93] [94] The metabolite quinone methide is obtained by loss of sulfate from nevirapine-12-sulfate and is a reactive electrophile [92] that forms a GSH adduct derived from the addition reaction of its sulfhydryl nucleophile. [95] Therefore, it is expected that this metabolite also can react directly with biomacromolecules such as DNA, yielding covalent adducts. "
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    ABSTRACT: Cytochrome P450 (CYP) is a super family of phase I enzyme in the biotransformation of xenobiotics and medications. Most medications undergo deactivation by CYP, and then are eliminated through either bile or kidneys from the body. CYP isozymes play a crucial role in drug interactions that may result in enhanced toxicity, reduced efficacy or onset of adverse reactions. On the other hand, many agents affecting CYP expression and activity may alter metabolic rate of different medications co-administrated. Therefore, the molecular basis, regulation by inducers or inhibitors, and pharmacologic reaction of specific CYP isozymes are the key issues of biochemical mechanisms, pharmaceutical development and safe use of various medications. This book is to meet the needs from basic molecular biochemists, pharmacologists, pharmacists, medical students, clinical practitioners and scientists, as well as broad readers who wish to understand how an herbal extract, medication or natural supplement is metabolized or transformed in the liver or other sites for deactivation and elimination. Special focuses are paid to herbal extracts and medications in the treatment of neuro-psychiatric or cardiovascular disorders, diabetes and viral hepatitis. Detailed dissection of drug interactions in a particular field intends to provide rationales for useful guidance of safe drug use in daily practice. The contributing authors are basic scientists, pharmacists, pharmacologists and on-service physicians in cardiovascular, neuro-psychiatric, gastroenterologic and hepatologic fields from Europe (Germany, France, Portugal), Australia, the US and China. Thus, the book is the collection of master pieces by well-known experts from various regions of the world, and represents the current understanding of CYP enzyme reaction and a contemporary coverage of possible drug interactions in involved fields. The featured chapters are scientific elucidation of basic biochemistry, pharmacology and clinical investigations in the interest of drug metabolism, interaction and safe use guidance in the single focus of this microsomal enzyme with multi-facet metabolic function.
    First edited by Jian Wu, 09/2014; Nova Science Publishers, Inc.., ISBN: 978-1-61942-209-4
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    • "Presently, it is not known whether genetic polymorphisms of the liver enzyme purported to be responsible for detoxifying the kavalactones (Cytochrome P450 2D6; CYP 2D6) modify any potential side effects (Sarris et al., 2009a, 2009b, 2009c). Individuals who are classified as poor or extensive metabolizers (via CYP 2D6 polymorphisms ) may have differing rates of adverse effects (AEs) from kava, as seen in other medications, due to differing pharmacokinetics (Zhou, 2009). Additionally, nothing is known about whether taking a regular medicinal dose of * Correspondence to: "
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    ABSTRACT: Presently, little is known about a number issues concerning kava (Piper methysticum), including (i) whether kava has any withdrawal or addictive effects; (ii) if genetic polymorphisms of the cytochrome (CYP) P450 2D6 liver enzyme moderates any potential adverse effects; and (iii) if medicinal application of kava has any negative or beneficial effect on sexual function and experience. The study design was a 6-week, double-blind, randomized controlled trial (n = 75) involving chronic administration of kava (one tablet of kava twice per day; 120 mg of kavalactones per day, titrated in non-response to two tablets of kava twice per day; 240 mg of kavalactones) or placebo for participants with generalized anxiety disorder. Results showed no significant differences across groups for liver function tests, nor were there any significant adverse reactions that could be attributed to kava. No differences in withdrawal or addiction were found between groups. Interesting, kava significantly increased female's sexual drive compared to placebo (p = 0.040) on a sub-domain of the Arizona Sexual Experience Scale (ASEX), with no negative effects seen in males. Further, it was found that there was a highly significant correlation between ASEX reduction (improved sexual function and performance) and anxiety reduction in the whole sample. Copyright © 2013 John Wiley & Sons, Ltd.
    Phytotherapy Research 11/2013; 27(11). DOI:10.1002/ptr.4916 · 2.40 Impact Factor
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    • "Genetic variation of drug metabolizing enzymes also has been shown as one of the major causes of the inter-individual variability to drug response. Therefore the impact of CYP2D6 polymorphism on the clearance of or response to a series of cardiovascular drugs was addressed (Zhou, 2009). Although the frequencies of CYP2D6 mutant alleles have been studied extensively in different populations, limited information is available for those of the Middle East populations. "
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    ABSTRACT: Background Hypertension is a cardiovascular disease that is affected by environmental, demographic and genetic factors. Objective This study aims to determine the frequency of the CYP2D6∗1, ∗3, ∗4 and ∗5 variants among hypertensive cases and cases with obesity and cases with cardiac complications. Subjects and methods DNA was isolated from peripheral blood samples that were collected from 123 hypertensive cases and from 429 healthy non-related controls by using the Magna pure system. Genomic DNA was used to determine the frequency of CYP2D6∗1, CYP2D6∗3, CYP2D6∗4 and CYP2D6∗5 allelic variants by the application of the light cycler polymerase chain reaction (Realtime PCR) technique. Results Comparing cases of hypertension and controls as regard to the genotypic allelic variants of CYP2D6 gene, hypertensive cases showed a significantly higher wild genotype 1/1 compared to controls (85.4% vs. 74.8%, p = 0.01) with a lower frequency of mutant genotype 4/4 (1.6% vs. 8.6%, p = 0.008) This phenomenon was manifested among cases of subgroups with obesity that had significantly lower mutant homozygous forms than obese controls (2.3% vs. 9.5%, p 0.04) and cases with cardiac complications (88.2% vs. 74.8%, p = 0.01). Conclusion CYP2D6 polymorphism is positively associated with hypertensive cardiac complications as well as hypertensive obese cases.
    08/2013; 66(4). DOI:10.1016/j.jobaz.2012.12.002
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