Chapter 8. Pharmacogenetics

General issues

Pharmacogenetics is the study of individual differences in the response to drugs, which are determined by allelic variations in genes controlling drug metabolism, efficacy, and toxicity. This branch of environmental medical genetics and clinical pharmacology arose out of a practical need to understand the complications of drug treatment. Data on adverse drug reactions were collected in the field of clinical pharmacology, while medical genetics was concerned with deciphering the mechanisms of their occurrence.

The doctors may face with patient’s individual hypersensitivity to the drug (similar to an overdose effect), although the patient is prescribed a dose appropriate for his age and sex; with partial or complete person’s drug tolerance, even if the dose was increased; with paradoxical drug reactions including complications that differ much from those determined by mechanisms of drug action.

The basic pharmacogenetics principles were formulated between 1950 and 1970. The term “pharmacogenetics” was first introduced by the German scientist F. Vogel in 1958. The development of pharmacogenetics relied on the registration of adverse drug reactions and their analysis, initially by clinical genealogical and twin methods and then by molecular genetic methods. The simultaneous studies of the final pathological phenotype and biochemical phases of drug metabolism enabled to understand the essence of adverse drug reactions and their principal stages.

Human genetic diversity underlies individual differences in the biotransformation of xenobiotics including drugs (see Chapter 7). Therefore, the theoretical basis of pharmacogenetics is rooted in functional human genomics, specifically, in information on gene polymorphisms involved in the drug biotransformation and genetic control of drug-drug interactions. Thus, the main task of pharmacogenetics is the study of allelic variants of genes that determine the individual characteristics of the pharmacokinetic and pharmacodynamic characteristics of the organism.

Due to the progress made in decoding the human genome and achievements in the pharmacology field, pharmacogenetics now is at the center of personalized medicine (individualized treatment).

Individual variation in drug response occurs in two pathways. The first is realized through pharmacokinetic processes (absorption, transport, metabolism and excretion of the drug or its metabolites). The second involves the pharmacodynamics of the drug. The differences observed in targets (receptors, enzymes) or metabolic pathways are determined by allelic variations. Consequently, pharmacogenetics is a broad study of any genetically determined variability in drug efficacy and toxicity.

The understanding of the pharmacogenetic patterns requires mastering the principles of xenobiotic biotransformation (or metabolism), described in Chapter 7.

All stages of drug biotransformation are carried out by appropriate enzymes and proteins. The most important of them are listed in Table 8.1.

Table 8.1. Enzymes and proteins involved in drug biotransformation

Note. DPYD — dihydropyrimidine dehydrogenase; SULT — sulfotransferase.

Genetic polymorphism defines three main phenotypes of metabolizers (individuals taking medications): extensive, slow, and rapid.

Extensive metabolizers are individuals with a normal metabolic rate of the drug of interest. Most people belong to this group, the majority are homozygous for the wild allele of the corresponding enzyme.

Slow metabolizers (sometimes null) are characterized by a reduced metabolic rate of the drug of interest. From a genetic viewpoint, they are homozygotes (with an autosomal recessive mode of inheritance) or heterozygotes (with an autosomal dominant mode of inheritance) for the mutant (“slow”) allele of the corresponding enzyme. These individuals show an inability to synthesize enzyme or synthesize it in inactive (or defective) form, thus they are predisposed to drug accumulation and adverse effects. Therefore, slow metabolizers undoubtedly require a reduction in drug dosage or its substitution.

Rapid (or overactive) metabolizers are characterized by an increased metabolic rate of certain drugs. Essentially these are homozygotes (with an autosomal recessive type of inheritance) or heterozygotes (with an autosomal dominant type of inheritance) for the “fast” allele of the corresponding enzyme. The individuals who carry copies of functional alleles, which also result in increased drug metabolism, are quite common. Rapid metabolizers eliminate the drug administered in standard doses very quickly, and the therapeutic concentration of the drug in the blood may not be reached; therefore, they require higher doses of drugs than normal metabolizers.