Drug metabolizing enzyme activities versus genetic variances for drug of clinical pharmacogenomic relevance

Pharmacogenomics is an important tool for the personalization of medical therapeutics. The determination of an individual's genotype for key enzymes that participate in the transportation, metabolism, and clearance is a strong determinant of therapeutic efficacy and toxicity avoidance. Regarding drug metabolism, subjects who have no or slower rate of enzyme activity than normal have higher circulation drug concentrations and are vulnerable to toxicity when the standard dosage is used. Individuals who have a faster of enzyme activity have lower circulating drug concentrations and may be sub-therapeutic at standard dosage. The situation is reversed for medications (prodrugs) that require enzymatic activation; poor metabolizers are unable to produce substantial quantities of bioactive drugs and rapid metabolizers produce too much. The optimum use of therapeutic drugs requires some knowledge of enzyme catabolic rates and how it affects the activation, inactivation, or clearance. The relationship between enzyme activity and pharmacogenomics has been extensively reviewed, e.g., the reader is referred to a recent Laboratory Medicine Practice Guidelines prepared by the National Academy of Clinical Biochemistry (NACB) [1].In a living person, it is difficult if not impossible to determine the phenotype of an individual for a specific hepatic enzyme due to the inability to obtain liver tissue. With the exception of thiopurine methyltransferase, the analysis of activity from blood is not a surrogate of tissue enzyme activity, as it is only a reflection of tissue necrosis and turnover. Measurement of the rate of substrate metabolism and/or product formation is therefore used to the assess phenotypes. This requires the subject to have taken the drug, either in single dosage or at steady state. Accurate assessments also require that the subject be free of other influences such as co-medications that can induce or inhibit hepatic gene expression or enzyme activity. The analysis of