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Inheritance and Drug Response
Introduction
Pharmacogenetics is the study of the inheritance influence on variation in drug response in different individuals. Although individual drug-response variation can be impacted by other factors such as sex, drug interactions, or age, genetic factors also have influence on the likelihood of drug adverse effects and drug efficacy. Genetic variation can influence drug response in all processes, including absorption, distribution, target interaction, metabolism, and excretion. However, this article mainly focuses on the concepts of pharmacogenetics in relation to drug metabolism. Nevertheless, the same principles apply to some inherited variations in the absorption, distribution, and interaction with therapeutic targets. Therefore, inherited variations that affect drug response are common, making it easy to incorporate pharmacogenetics into clinical practice.
Background Information
The origin of the concept of pharmacogenetics was a clinical observation that showed varied plasma and urine concentrations of a given drug in different individuals. Later, it was discovered that the genes causing the variation were inherited. Then, the enzymes that metabolize drugs were identified. In further, it was followed by the identification of genes that coded for DNA-sequence variation resulting in drug response variation. Majority of the pharmacogenetic characteristics that were initially identified consisted of a single gene and the allele(s).. Succinylcholine and isoniazid were the first drugs used to demonstrate the influence of inheritance on drugs leading to the acceptance of the concept of pharmacogenetics.
Pharmacogenetics of Drug Metabolism
The role of metabolism is to convert drugs to more water-soluble metabolites for easier excretion. Drugs metabolism has got two paths, namely phase I and phase II. Phase I involves reactions such as hydrolysis, oxidation, and reduction. On the other hand, phase II reactions include acetylation, methylation, glucuronidation, and sulfation. Polymorphism of inherited genes causes impairment of enzymes involved in reactions of both phase I and II, resulting in variation in drug response among individuals. Each phase has enzymes that metabolize the drugs involved. Cytochrome P-450 2D6 (CYP2D6) is a good example of such enzymes and is involved in the metabolism of drugs, such as s codeine, metoprolol, nortriptyline and dextromethorphan in phase I. On the other hand, enzyme thiopurine S-methyltransferase (TPMT) is involved in the metabolism of thiopurines in phase II by S-methylation. The genetic polymorphism of genes coding for these enzymes leads to the inheritance of genes that encode for an enzyme with either reduced activity or with no activity at all, causing poor metabolism of the drugs involved. Such subjects will have higher plasma concentration of the parent drug and lower urinary concentrations of metabolites. However, some individuals can inherit multiple copies of these genes, leading to ultrarapid metabolism. Such individuals can demonstrate an inadequate therapeutic response to standard drug doses typically metabolized by normal enzymes. Pharmacogenetic variation in drugs response is mostly linked to drugs with narrow therapeutic indexes. Pharmacogenetic studies utilize the use of prodrugs to divide individuals into either having an extensive metabolism or having a poor metabolism.
Conclusion
The convergence of pharmacogenetics and human genomics advancements has led to the birth of pharmacogenomics. With the continued research in the human genome, there is a likelihood of discovery of all genes that encode for enzymes that catalyze drug metabolism in phase I and II. This discovery is expected to spill over to even the genes encoding for drug distributors and drug interaction targets. Convergence of pharmacogenetics and human genomics advancements has enhanced physicians to individualize therapy with certain drugs. Physicians can now select optimal dose of the best drug to use in each patient depending on their extent of genetic variation and hence the variation in drug response.