Pharmacogenetics

PHARMACOGENETICS

Pharmacogenetics is the study of genetic factors related to human variability in response to medicines. Its modern root lies in the work of Archibald Garrod, whose work on alcaptonuria in 1902 comprised the first proof of Mendel’s laws of genetics in humans. Garrod hypothesized that adverse reactions after drug ingestion could result from genetically determined differences in bio-chemical processes and further suggested that enzymes play a role in the detoxifi-cation of foreign substances and that the lack of an enzyme in an individual might cause that mechanism to fail (Garrod, 1902).

Incidental clinical observations during the late 1940s and 1950s resulted in the discovery of several relatively common genetic variations related to ADRs. Hemolysis related to anti-malarial treatment was much more common among African-American soldiers during World War II, leading to the identi-fication of inherited variants of glucose-6-phosphate dehydrogenase (G-6-PD). Prolonged muscle relax-ation and apnea after suxamethonium was found to be caused by an inherited deficiency of a plasma cholinesterase. Peripheral neuropathy was observed in a significant number of patients treated with the anti-tuberculosis drug isoniazid, leading to the identifica-tion of genetic differences in acetylation pathways.

The genetic variations related to these observations are called polymorphisms-inter-individual differences in DNA sequences at a specific chromosomal loca-tion that exist at a frequency of more than 1% in the general population. The two alleles (alternate forms of a gene) present at a given gene locus comprise the genotype, which now can be characterized at the DNA level. The progress of The Human Genome Project and advances in genomic technology enhance the like-lihood that genetic markers that predict a percent-age of adverse events, including lack of efficacy will be identified, validated and offered to the public in the next 5–10 years.

The influence of genotype on phenotype (observ-able features resulting from the action of one or more genes) – in this case, the influence of genes on drug kinetics or dynamics – now can be measured using advanced analytical methods for metabolite detec-tion and clinical investigation tools such as receptor-density studies by positron emission tomography (Meyer, 2000).

The FDA approved the first commercially available kit to measure some P450 polymorphisms in 2004, thus moving the delivery of genetic tests that can affect drug response to be more readily available to clinical practice.

Pharmacogenetic mechanisms related to polymor-phisms can result in clinically relevant sequelae in at least three ways:

•   through genes associated with altered drug metabolism and transport: increased or decreased metabolism of a drug can affect the concentration of the drug and its active, inactive and toxic metabo-lites (e.g. metabolism of tricyclic anti-depressants),

•   through genes associated with unexpected drug effects (e.g. haemolysis in G-6-PD deficiency) and

•   through genes associated with genetic variation in  drug  targets,  resulting  in  altered  clinical response  and  frequency  of  ADRs  (e.g.   2-adrenergic receptor variants and altered response to 3-agonists in asthmatic patients) (Meyer, 2000).

Inherited variations related to drug metabolism generally are monogenic (single gene) traits, and their clinical relevance in terms of pharmacokinetics and dynamics depends on their importance for the acti- vation or inactivation of drug substrates (Evans and Relling, 1999). The most important effects include toxicity for medicines that have a narrow therapeu- tic window and are inactivated by a polymorphic enzyme (e.g. thioguanine, flourouracil, mercaptop- urine and azathioprine) and decreased efficacy of medicines that require activation by an enzyme that exhibits a polymorphism (e.g. codeine). These vari- ant genes and the enzymes they code for also may be involved in some drug–drug interactions. Most of these monogenic traits have been identified on the basis of dramatic observed differences in response (efficacy and toxicity) among individuals. Although still not in common clinical use, functional enzyme analyses or genotyping to detect some of the common monogenic traits affecting drug metabolism are begin- ning to be used more frequently, especially in the field of cancer chemotherapy (Iyer and Ratain, 1998; Mancinelli, Cronin and Sadee, 2000).

The FDA has begun to include more pharmacoge- netic data into the drug labels of medicines. Accord- ing to Dr. Larry Lesko, 35% of all drugs have some pharmacogenetic data included in their drug label. In 2003–04, the labels of several medicines were modified to reflect the risks associated with certain genotypes. Azathioprine, 6-mercaptopurine, thiogua- nine and irinotecan have information about genotype effects on drug safety in their labels. Thioridazine has a black box warning related to P450 2D6 poor metab- olizers. Strattera, a drug for attention deficit hyperac- tivity disorder also lists the drug–genotype interaction prominently in its drug label.

Although these monogenic traits affecting drug metabolism are important, the overall pharmacologic effects of drugs are more likely to be related to the interaction of several genes (polygenic), all encod- ing proteins that are involved in multiple pathways of metabolism, transport, disposition and action (Evans and Relling, 1999). These polygenic traits, which also may play a role in drug–drug interactions, are more challenging to uncover during clinical trials, espe- cially when the mechanisms of drug metabolism and action are unknown. In contrast with the past, when clinical observations of individual differences in drug response prompted biochemical and genetic research into the underlying causes, recent advances in molec- ular sequencing technology may reverse that process: laboratory identification of polymorphisms (espe- cially those in gene regulatory or coding regions) may be the initiating observation, followed by biochemical and human studies to ascertain their phenotypic and clinical consequences (Evans and Relling, 1999).

Continued research in pharmacogenetics has the potential to result in the elucidation of the genetic basis of drug metabolism, disposition and response. In some cases, the results of research may provide clinicians with the ability to subclassify patients using pharmacogenetic-based diagnostic criteria. If research efforts are successful, then it will become possible, in many circumstances, to select medicines and deter- mine appropriate dosing on the basis of an individual patient’s inherited ability to metabolize and respond to specific drugs, thus reducing the enormous individ- ual, societal and economic burdens currently related to treatment failures and ADRS.

The US National Institute of General Medical Sciences (NIGMS) and other components of the National Institutes of Health (NIH) are sponsoring a major research initiative, the Pharmacogenetics Research Network, to reach this goal. This network, established in 2000, initially comprised nine teams of investigators across the United States, with research projects including asthma treatments, tamoxifen and other cancer drugs, ethnic differences in response to anti-depressants, drug transporters, database design and ethical, legal and social ramifications of pharmacogenetic research (http://www.nigms.nih.gov/ PGRN.Network/Pharmacogeneticworkinggroup.htm).