117Genetically Determined Adverse Drug Reactions
One reason for the high incidence of serious and fatal ADRs is that the existing drug
development does not incorporate genetic variability in pharmacokinetics and phar-
macodynamics of new drug candidates. Polymorphisms in the genes that code for
drug-metabolizing enzymes, drug transporters, drug receptors, and ion channels can
affect an individual’s risk of having an adverse drug reaction, or can alter the effi -
cacy of drug treatment in that individual. Mutant alleles at a single gene locus are
the best studied individual risk factors for adverse drug reactions, and include many
genes coding for drug-metabolizing enzymes. These genetic polymorphisms of
drug metabolism produce the phenotypes of “poor metabolizers” or “ultrarapid
metabolizers” of numerous drugs. Together, such phenotypes make up a substantial
proportion of the population. Genetic aberrations associated with adverse reactions
are of two types. The vast majority arise from classical polymorphism in which the
abnormal gene has a prevalence of more than 1 % in the general population. Toxicity
is likely to be related to blood drug concentration and, by implication, to target
organ concentration as a result of impaired metabolism. The other type is rare and
only 1 in 10,000 to 1 in 100,000 persons may be affected. Most idiosyncratic drug
reactions fall into the latter category. Mutant alleles at a single gene locus are the
best studied individual risk factors for adverse drug reactions, including the genes
for N-acetyltransferases, thiopurine methyltransferase, dihydropyrimidine dehydro-
genase, and cytochrome P450. However, pharmacogenetic factors rarely act alone;
rather they produce a phenotype in concert with other variant genes such as those
for receptors and with environmental factors such as cigarette smoking. Examples
of adverse reactions with a pharmacogenetic basis are shown in Table 4.7 and this
can form the basis of practice of genotyping prior to decision to use a drug that
might produce serious adverse reactions.
Most idiosyncratic drug reactions are unpredictable and because of their rarity
my not show up in patients during clinical trials with a few thousand patients. They
may fi rst surface when the drug has been taken by hundreds of thousands of patients
in the post-marketing phase. Pharmacogenetics, by individualizing treatment to
patients for whom it is safe, provides a rational framework to minimize the uncer-
tainty in outcome of drug therapy and clinical trials and thereby should signifi cantly
reduce the risk of drug toxicity.
Topiramate, an anticonvulsant medication, is an effi cacious treatment for alcohol
dependence. A study has examined three SNPs of the glutamate receptor GluR5
gene (GRIK1) as predictors of topiramate-induced side effects in the context of a
laboratory study of topiramate (Ray et al. 2009 ). Analyses revealed that an SNP in
intron 9 of the GRIK1 gene (rs2832407) was associated with the severity of
topiramate- induced side effects and with serum levels of topiramate. Genes under-
lying glutamatergic neurotransmission, such as the GRIK1 gene, may help predict
heterogeneity in topiramate-induced side effects. Future studies in larger samples
are needed to more fully establish these preliminary fi ndings.
Role of Pharmacogenetics in Pharmaceutical Industry