Codeine is bioactivated to morphine, a strong opioid agonist, by the hepatic cytochrome P450 2D6 (CYP2D6); hence, the efficacy and safety of codeine as an analgesic are governed by CYP2D6 ...polymorphisms. Codeine has little therapeutic effect in patients who are CYP2D6 poor metabolizers, whereas the risk of morphine toxicity is higher in ultrarapid metabolizers. The purpose of this guideline (periodically updated at http://www.pharmgkb.org) is to provide information relating to the interpretation of CYP2D6 genotype test results to guide the dosing of codeine.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Codeine is bioactivated to morphine, a strong opioid agonist, by the hepatic cytochrome P450 2D6 (CYP2D6); hence, the efficacy and safety of codeine are governed by CYP2D6 activity. Polymorphisms are ...a major cause of CYP2D6 variability. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for codeine based on CYP2D6 genotype. This document is an update to the 2012 Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for CYP2D6 genotype and codeine therapy.
Clinical Pharmacology & Therapeutics (2014); 95 4, 376–382. doi:10.1038/clpt.2013.254
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Selective serotonin reuptake inhibitors (SSRIs) are primary treatment options for major depressive and anxiety disorders. CYP2D6 and CYP2C19 polymorphisms can influence the metabolism of SSRIs, ...thereby affecting drug efficacy and safety. We summarize evidence from the published literature supporting these associations and provide dosing recommendations for fluvoxamine, paroxetine, citalopram, escitalopram, and sertraline based on CYP2D6 and/or CYP2C19 genotype (updates at www.pharmgkb.org).
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Polymorphisms in CYP2D6 and CYP2C19 affect the efficacy and safety of tricyclics, with some drugs being affected by CYP2D6 only, and others by both polymorphic enzymes. Amitriptyline, clomipramine, ...doxepin, imipramine, and trimipramine are demethylated by CYP2C19 to pharmacologically active metabolites. These drugs and their metabolites, along with desipramine and nortriptyline, undergo hydroxylation by CYP2D6 to less active metabolites. Evidence from published literature is presented for CYP2D6 and CYP2C19 genotype–directed dosing of tricyclic antidepressants.
Clinical Pharmacology & Therapeutics (2013); 93 5, 402–408. doi:10.1038/clpt.2013.2
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CYP2D6
and
CYP2C19
polymorphisms affect the exposure, efficacy and safety of tricyclic antidepressants (TCAs), with some drugs being affected by CYP2D6 only (e.g., nortriptyline and desipramine) and ...others by both polymorphic enzymes (e.g., amitriptyline, clomipramine, doxepin, imipramine, and trimipramine). Evidence is presented for
CYP2D6
and
CYP2C19
genotype-directed dosing of TCAs. This document is an update to the 2012 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for
CYP2D6
and
CYP2C19
Genotypes and Dosing of Tricyclic Antidepressants.
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Antiestrogens include agents such as tamoxifen, toremifene, raloxifene, and fulvestrant. Currently, tamoxifen is the only drug approved for use in breast cancer chemoprevention, and it remains the ...treatment of choice for most women with hormone receptor positive, invasive breast carcinoma. While antiestrogens have been available since the early 1970s, we still do not fully understand their mechanisms of action and resistance. Essentially, two forms of antiestrogen resistance occur: de novo resistance and acquired resistance. Absence of estrogen receptor (ER) expression is the most common de novo resistance mechanism, whereas a complete loss of ER expression is not common in acquired resistance. Antiestrogen unresponsiveness appears to be the major acquired resistance phenotype, with a switch to an antiestrogen-stimulated growth being a minor phenotype. Since antiestrogens compete with estrogens for binding to ER, clinical response to antiestrogens may be affected by exogenous estrogenic exposures. Such exposures include estrogenic hormone replacement therapies and dietary and environmental exposures that directly or indirectly increase a tumor's estrogenic environment. Whether antiestrogen resistance can be conferred by a switch from predominantly ERalpha to ERbeta expression remains unanswered, but predicting response to antiestrogen therapy requires only measurement of ERalpha expression. The role of altered receptor coactivator or corepressor expression in antiestrogen resistance also is unclear, and understanding their roles may be confounded by their ubiquitous expression and functional redundancy. We have proposed a gene network approach to exploring the mechanistic aspects of antiestrogen resistance. Using transcriptome and proteome analyses, we have begun to identify candidate genes that comprise one component of a larger, putative gene network. These candidate genes include NFkappaB, interferon regulatory factor-1, nucleophosmin, and the X-box binding protein-1. The network also may involve signaling through ras and MAPK, implicating crosstalk with growth factors and cytokines. Ultimately, signaling affects the expression/function of the proliferation and/or apoptotic machineries.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Developmental changes in the liver can significantly impact drug disposition. Due to the emergence of microRNAs (miRNAs) as important regulators of drug disposition gene expression, we studied ...age‐dependent changes in miRNA expression. Expression of 533 miRNAs was measured in 90 human liver tissues (fetal, pediatric 1–17 years, and adult 28–80 years; n = 30 each). In all, 114 miRNAs were upregulated and 72 were downregulated from fetal to pediatric, and 2 and 3, respectively, from pediatric to adult. Among the developmentally changing miRNAs, 99 miRNA‐mRNA interactions were predicted or experimentally validated (e.g., hsa‐miR‐125b‐5p‐CYP1A1; hsa‐miR‐34a‐5p‐HNF4A). In human liver samples (n = 10 each), analyzed by RNA‐sequencing, significant negative correlations were observed between the expression of >1,000 miRNAs and mRNAs of drug disposition and regulatory genes. Our data suggest a mechanism for the marked changes in hepatic gene expression between the fetal and pediatric developmental periods, and support a role for these age‐dependent miRNAs in regulating drug disposition.
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Metoprolol is a selective β‐1 adrenergic receptor blocker that undergoes extensive metabolism by the polymorphic enzyme cytochrome P450 2D6 (CYP2D6). Our objective was to investigate the influence of ...CYP2D6 polymorphisms on the efficacy and tolerability of metoprolol tartrate. Two hundred and eighty‐one participants with uncomplicated hypertension received 50 mg of metoprolol twice daily followed by response‐guided titration to 100 mg twice daily. Phenotypes were assigned based on results of CYP2D6 genotyping and copy number variation assays. Clinical response to metoprolol and adverse effect rates were analyzed in relation to CYP2D6 phenotypes using appropriate statistical tests. Heart rate response differed significantly by CYP2D6 phenotype (P < 0.0001), with poor and intermediate metabolizers showing greater reduction. However, blood pressure response and adverse effect rates were not significantly different by CYP2D6 phenotype. Other than a significant difference in heart rate response, CYP2D6 polymorphisms were not determinants of variability in metoprolol response or tolerability.
Clinical Pharmacology & Therapeutics (2014); 96 2, 175–181. doi:10.1038/clpt.2014.62
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Hospital systems increasingly utilize pharmacogenomic testing to inform clinical prescribing. Successful implementation efforts have been modeled at many academic centers. In contrast, this report ...provides insights into the formation of a pharmacogenomics consultation service at a safety‐net hospital, which predominantly serves low‐income, uninsured, and vulnerable populations. The report describes the INdiana GENomics Implementation: an Opportunity for the UnderServed (INGENIOUS) trial and addresses concerns of adjudication, credentialing, and funding.
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