The Use of Microdosing for In vivo Phenotyping of Cytochrome P450 Enzymes: Where Do We Stand? A Narrative Review
L. T. van der Heijden, F. Opdam, J. H. Beijnen, A. Huitema
European Journal of Drug Metabolism and Pharmacokinetics April 30, 2024 DOI: 10.1007/s13318-024-00896-2 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Microdosing |
| Key findings | Microdosing can be used for in vivo phenotyping of CYP2C19 and CYP3A but is not recommended for CYP1A2, CYP2C9, CYP2D6, or CYP2E1. |
Abstract
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 (AUC0–24) 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 (AUC0–10) and AUC from 2 to 4 h (AUC2–4).
Comparable studies
Other narrative reviews on microdosing, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Big physics, small doses: the use of AMS and PET in human microdosing of development drugs | 2003 | Review | |
| Phase 0/microdosing approaches: time for mainstream application in drug development? | 2020 | Review | |
| Microdosing and drug development: past, present and future | 2013 | Review | |
| Microdosing and Other Phase 0 Clinical Trials: Facilitating Translation in Drug Development | 2016 | Review | |
| Expectancy Effects in Psychedelic Trials. | 2024 | Review |
Citations in the library
Cites 6
- Use of microdosing to predict pharmacokinetics at the therapeutic dose: Experience with 5 drugs Clinical Pharmacology & Therapeutics September 1, 2006
- Identification of the Rate-Determining Process in the Hepatic Clearance of Atorvastatin in a Clinical Cassette Microdosing Study Clinical Pharmacology & Therapeutics August 10, 2011
- Microdosing and drug development: past, present and future Expert Opinion on Drug Metabolism & Toxicology April 4, 2013
- The utility of microdosing over the past 5 years Expert Opinion on Drug Metabolism & Toxicology November 28, 2008
- Nonlinear Pharmacokinetics of Oral Quinidine and Verapamil in Healthy Subjects: A Clinical Microdosing Study Clinical Pharmacology & Therapeutics June 29, 2011
and 1 more in the library