Pharmacogenomics aims to predict how individual genetic variability impacts drug absorption, metabolism and activity. While one treatment approach may work well for one individual, the same approach may not be effective or may cause adverse drug effects in other patients1,2
The costs of adverse drug effects
Membrane transporters are crucial determinants of drug absorption. The OATP family (organic anion transporting polypeptides) of transporters is especially important in mediating hepatocyte uptake of many drugs. The genetic variability in the genes encoding these transporters has been linked to significant differences in the pharmacokinetics of drug absorption. For example, a single nucleotide polymorphism in the SLCO1B1 gene (encodes OATP1B1) can lead to the impaired absorption of many statins, including simvastatin acid, pitavastatin, atorvastatin and rosuvastatin7. In addition, the resulting high plasma concentration of simvastatin has also been associated with an increased risk of drug-induced myopathy8.
The metabolizer phenotypes
Patients that carry variants associated with elevated drug metabolism (ultra-fast metabolizers) can benefit from higher doses in order to achieve therapeutic effects. On the other hand, patients that carry variants resulting in poor drug metabolism are at risk for toxicity and more than twice as likely to display adverse drug effects3. For example, three different CYP2C19 variants correlate to a reduced ability to metabolize antiplatelet agent clopidogrel and carriers are at increased risk for adverse cardiovascular events3. A recent study focused on one of the three variants (CYP2C19*2) and showed carriers exhibited a 2 fold greater risk of a cardiovascular ischemic event or death during a 1-year follow up period9. In response to mounting evidence, the FDA now recommends prescribers consider alternative treatment options for patients in the poor metabolizer category.
A higher incidence of toxicity for poor metabolizers has also been reported with a number of antidepressants, including desipramine, venlafaxine, amitriptyline and haloperidol. In addition, specific CYP2D6 polymorphisms can inhibit the analgesic effects of pro-drug opioid medication such as codeine, tramadol and oxycodone3. Conversely, ultra-fast metabolizers can experience life-threatening toxicity with the same opioids.
Drug activity can also be affected by genetic variability associated with the biological drug targets. For example, warfarin targets the VKOR1C1 gene product, K-epoxide reductase. This enzyme mediates the production of active vitamin K, an essential blood clotting factor. Warfarin and other related anticoagulants inhibit K-epoxide reductase activity in order to prevent or treat thromboembolic events10. A commonly occurring VKORC1 variant (1639G>A) potentiates the effects of warfarin and as a result, a lower starting dose is recommended for these patients. In addition, the relative frequency of the variant allele at the population level has been shown to explain differences in the optimal dosing requirements between Caucasian, black and Asian patients11.
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Wang, L., McLeod, H. L. & Weinshilboum, R. M. Genomics and drug response. The New England journal of medicine364, 1144-1153, doi:10.1056/NEJMra1010600 (2011).
Samer, C. F., Lorenzini, K. I., Rollason, V., Daali, Y. & Desmeules, J. A. Applications of CYP450 testing in the clinical setting. Molecular diagnosis & therapy17, 165-184, doi:10.1007/s40291-013-0028-5 (2013).
Lazarou, J., Pomeranz, B. H. & Corey, P. N. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA: the journal of the American Medical Association279, 1200-1205 (1998).
Van Driest, S. L. et al. Clinically actionable genotypes among 10,000 patients with preemptive pharmacogenomic testing. Clinical pharmacology and therapeutics95, 423-431, doi:10.1038/clpt.2013.229 (2014).
Epstein, R. S. et al. Warfarin genotyping reduces hospitalization rates results from the MM-WES (Medco-Mayo Warfarin Effectiveness study). Journal of the American College of Cardiology55, 2804-2812, doi:10.1016/j.jacc.2010.03.009 (2010).
Kalliokoski, A. & Niemi, M. Impact of OATP transporters on pharmacokinetics. British journal of pharmacology158, 693-705, doi:10.1111/j.1476-5381.2009.00430.x (2009).
Group, S. C. et al. SLCO1B1 variants and statin-induced myopathy–a genomewide study. The New England journal of medicine359, 789-799, doi:10.1056/NEJMoa0801936 (2008).
Shuldiner, A. R. et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA : the journal of the American Medical Association302, 849-857, doi:10.1001/jama.2009.1232 (2009).
Rost, S. et al. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature427, 537-541, doi:10.1038/nature02214 (2004).
Johnson, J. A. et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clinical pharmacology and therapeutics90, 625-629, doi:10.1038/clpt.2011.185 (2011).