USE OF PROBE DRUGS AS PREDICTORS OF DRUG-METABOLISM IN HUMANS

The pharmacokinetics of many drugs often vary considerably among indiv iduals, largely because of variations in the expression of different c ytochrome P-450 (CYP) enzymes in the liver and other tissues. Relative ly selective substrate probes in vivo have been discovered for several major CYP isoforms involved in oxidative drug metabolism. Regarding i soforms that show genetic polymorphism (CYP2C19 and CYP2D6), genotypin g as well as phenotyping with appropriate probe drugs can be used to d istinguish between ''poor'' and ''extensive'' metabolizers. Measuremen t of CYP2D6 activity which is being performed increasingly by means of genotyping, has an established role in the individualization of the d osage of selected CYP2D6 substrates. However, the therapeutic implicat ions of extremely high CYP2D6 activity in some patients (ultrarapid me tabolizers) need more attention. The therapeutic consequences of CYP2C 19 polymorphism are not as well characterized as those of CYP2D6 polym orphism, but are likely to be of little significance with most CYP2C19 substrates. Probe-based assays are also available for measurement of in vivo activity of CYP1A2, CYP2E1 and CYP3A4; those will be discussed in detail in this review. These tests can be used for example, to com pare the activity of a specific isoform among patients and to characte rize effects of such environmental factors as drugs and compounds in t he diet on enzyme activity. However, it should be recognized that atte mpts to develop valid probe-based assays of in vivo activity of specif ic, nonpolymorphic CYP isoforms have proved relatively difficult; for example, none of the several putative probes of CYP3A4, the most impor tant drug-metabolizing CYP isoform, is completely satisfactory. It is now clear that many diverse factors must be considered in the validati on of these tests.