Pharmacogenomics: Single Nucleotide Polymorphisms (SNPs) and Personalized Medicines

9 June, 1998

Pharmacogenomics: Single Nucleotide Polymorphisms (SNPs) and Personalized Medicines

New jargons are coined when new concepts and/or fields develop.
Pharmacogenetics is a field dating back to 1950s that studies genetic differences (polymorphisms) in drug metabolism and links them to the safety and efficacy of a therapeutic. There are relatively small number of drug-metabolizing enzymes: cytochrome P450 (CYP) isozymes, N-acetyl transferase (NAT) isozymes, UDP-glucuronosyl transferases and methyl transferases. For most drugs, CPY determines how long and how much of a drug remains in the body. For example, polymorphisms of CYP2D6, one of the 6 CYP isozymes, dictate slow or ultra-rapid metablolizers of antidepressants, antipsychotics, b-blockers, antiarrhythmics, etc and lead to systemic accumulation and toxicity. Increasing numer of drug makers characterize the role of the polymorphic P450s in drug discovery and development. But generally, physicians make empirical decisions about the types of treatment and drug dosage on the basis of population average. As humans show incredible genetic diversity, there still remain many deficiencies that pervade pharmaceutical development.

Pharmacogenomics is a field of molecular study of genetic factors that determine drug efficacy and toxicity. It is not for predisposition or predictive testing on the risk of a disease or its prognosis but rather concerned with genetic effects on drug themselves and with the genetic variances that contribute to the variable effects of drugs in different individuals. Pharmacogenomics is emerging from pharmacogenetics, being spurred forward by the data from Human Gemone Project that has already helped to accelerate drug discovery. It is highly likely that pharmacogenomic methods reduce clinical development times and costs, reveal new indications for existing drugs and ultimately generate personalized medicines.

Tacrine (Park-Davis, approved in 1993) may serve as an illustration of pharmacogemonics. Tacrine as a acetylcholine esterase inhibitor acts by raising levels of neurotransmitter acetylcholine which is depleted in the brains of Alzheimer's sufferers. In fact, only ca. 25% of the patients benefit from tacrine and another 25% suffer debilitating side effects such as liver toxicity, nausea, and vomiting (Poirer J et al., 1995: uid=96109245). As it turned out, patients of apolipoprotein E (APOE) genotype, APOE e4 (e4/e4), responded much more poorly to tacrine than those of other APOE genotypes. Alternatively, S12024 (INSERM, France) that increases brain noradrenergic/vasopressinergic activity benefit Alzheimer's sufferers of APOE e4 genotype (Richard F et al., 1997: uid=97200965). Molecular mechanisms underlining these results are not clear but pharmacogenomic methods are now getting widely used in developing treatments for neurodegenerative diseases.

Another jargon is SNPs ( "snips" for single nucleotide polymorphisms). NIH now plans with $ 20-30 million over 3 years to sequence "snippets" of DNA from 100-500 people in 4 major population categories: African, Asian, European, and Native American. The basic strategy is to collect ca. 100,000 single-base variations as landmarks for creating a fine-grained map of the human genome (Collins F, National Human Genome Institute). Biochips (Affimetrix/MIT) are being developed for ca 90% accuracy to find new SNPs in snippet DNA. Against a fine SNP map of the genome, SNPs of patients suffering specific diseases may be used to genotype them for clinical trials to improve the economy of drug development, and to rescue failed drugs due to the imbalance between efficacy and toxicity for the general population. SNPs may also form a Clinical Genetic Relational Database (Spectra Biomedical/Glaxo Wellcome) for seeking new indications for existing drugs. For example, polymorphisms in dopamine receptors are associated with the symptoms of migraine. Dopamine antagonists were not developed for migraine but now a subpopulation of migraine sufferers with the relevant polymorphisms may be treated with dopamine antagonists.

Perhaps one of the merits of pharmacogenomics for drug makers is that molecular mechanisms and/or functions of target molecules (pharmacodynamic factors) do not necessarily have to be known prior to drug development for specific diseases and as patients are expected to demand more of individual treatments, the new venue briefly mentioned here would give the opportunity leading to personalized medicines.　

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