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[Diagnosis of hepatic enzyme activities of drug metabolizing enzymes-phenotyping and genotyping].

Drug metabolizing enzymes (DMEs) play an important role in the biotransformation of various xenobiotics, generally by detoxifying and eliminating substrates by converting them to more hydrophilic derivatives, or in some cases, activating substrates by conversion to intermediates that are highly reactive with biological macromolecules. It is widely accepted that the enzymatic activities of hepatic DMEs are one of the most important determinants of the concentration of drugs at their site of action or in the blood. Wide inter-individual variability in drug concentrations in the blood has been demonstrated even after the administration of the same doses on the basis of body weight, and in many cases the wide differences in plasma drug concentrations have been attributed to the individual differences in the enzymatic activities of DMEs. Attempts have therefore been made to estimate the hepatic DME activities of each individual before administration of drugs clinically. Three different approaches were taken to estimate patients' hepatic DME activities: 1) the use of probe drugs (phenotyping); 2) molecular diagnosis of genetic DME deficiency (genotyping); 3) examination of DME levels/activities in peripheral blood leukocytes/lymphocytes on the assumption that their activities in leukocytes/lymphocytes are well correlated with hepatic enzyme activities. A great number of data have been accumulated concerning the specificity of certain DME for candidate probe drugs, and searches have been made for mutated alleles of DME genes that indicate whether an individual is deficient in DMEs. Gene expression is measured by sensitive methods such as the reverse-transcriptase polymerase chain reaction and/or immunochemical methods in peripheral blood leukocytes/lymphocytes, which are less invasive tissues. Knowledge is being accumulated that will allow the development of useful methods of predicting the activities of hepatic DMEs that affect individual pharmacokinetics/pharmacodynamics. In this article, various reported methods of assessing hepatic DME activities are reviewed for the purpose of maximizing the efficacy and safety of pharmacotherapy.