Tpmt

Figure 2.1 Pie chart. Most drug-metabolizing enzymes exhibit clinically relevant genetic polymorphisms. Essentially all of the major human enzymes responsible for modification of functional groups [classified as Phase I reactions (left)] or conjugation with endogenous substituents [classified as Phase II reactions (right)] exhibit common polymorphisms at the genomic level; those enzyme polymorphisms that have already been associated with changes in drug effects are separated from the corresponding pie charts. The percentage of Phase I and Phase II metabolism of drugs that each enzyme contributes is estimated by the relative size of each section of the corresponding chart.2 With permission from the American Association for the Advancement of Science.

metabolism on the predicted therapeutic outcome of a drug depends upon whether the drug is delivered in its active form or in an inactive prodrug form that requires metabolism for activation.

Drug responses that are influenced by genetic factors can often be identified by phenotypic or genotypic analysis. (1) Phenotypic analysis: drug responses that exhibit a multimodal distribution pattern (nonnormal distribution) are indicative of genetic influences on the drug response in the test population. (2) Drug response phenotype exhibits significant heritability in family pedigrees. Knowledge of genotype/phenotype allows for a more informed decision in managing pharmacogenetic disorders.

Conceptually, pharmacogenetics may be regarded as the third leg in the triad of factors that determine drug response (see Figure 2.2).

Physiological changes that accompany normal growth and development of infants and children and of aging persons add another level of variability to drug responses that must be considered in making clinical and therapeutic decisions. During the first months and years after birth, changes in body composition and organ function are cyclic or periodic and may be discordant in different tissues. During the middle years of life, these changes abate and homeostatic mechanisms maintain a functional equilibrium. In the elderly, person-to-person variability in drug response increases owing to a series of age-related asynchronous morphological and functional changes that occur in many organs and tissues. The prin-

Pharmacogenomics

Figure 2.2 Pharmacogenetics may be regarded as the third leg in the triad of factors that determine drug response.

ciples underlying age-appropriate adjustments in drug dosing to provide safe and effective pharmacotherapy are considered separately below.

Examples of Phase 1 and Phase 2 drug-metabolizing enzyme variants and their effect on response to exogenous chemicals are shown in the following.

Phase

Enzyme

Phenotype

Drugs / chemicals

Response

Phase 1

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