The Use of Microdosing for In vivo Phenotyping of Cytochrome P450 Enzymes: Where Do We Stand? A Narrative Review

Cytochrome P450 (CYP) enzymes play a central role in the elimination of approximately 80% of all clinically used drugs. Differences in CYP enzyme activity between individuals can contribute to interindividual variability in exposure and, therefore, treatment outcome. In vivo CYP enzyme activity could be determined with phenotyping. Currently, (sub)therapeutic doses are used for in vivo phenotyping, which can lead to side effects. The use of microdoses (100 µg) for in vivo phenotyping for CYP enzymes could overcome the limitations associated with the use of (sub)therapeutic doses of substrates. The aim of this review is to provide a critical overview of the application of microdosing for in vivo phenotyping of CYP enzymes. A literature search was performed to find drug–drug interaction studies of CYP enzyme substrates that used microdoses of the respective substrates. A substrate was deemed sensitive to changes in CYP enzyme activity when the pharmacokinetics of the substrate significantly changed during inhibition and induction of the enzyme. On the basis of the currently available evidence, the use of microdosing for in vivo phenotyping for subtypes CYP1A2, CYP2C9, CYP2D6, and CYP2E1 is not recommended. Microdosing can be used for the in vivo phenotyping of CYP2C19 and CYP3A. The recommended microdose phenotyping test for CYP2C19 is measuring the omeprazole area-under-the-concentration-time curve over 24 h (AUC_0–24) after administration of a single 100 µg dose. CYP3A activity could be best determined with a 0.1–75 µg dose of midazolam, and subsequently measuring AUC extrapolated to infinity (AUC_∞) or clearance. Moreover, there are two metrics available for midazolam using a limited sampling strategy: AUC over 10 h (AUC_0–10) and AUC from 2 to 4 h (AUC_2–4).