Perspective: 4β-hydroxycholesterol as an emerging endogenous biomarker of hepatic CYP3A
| Autor: | James McLeod, Jialin Mao, Yvonne S. Lin, Manoli Vourvahis, Iain Martin, Robert van Horn, Gail T. Nolan |
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| Rok vydání: | 2016 |
| Předmět: |
Hydrocortisone
CYP3A Midazolam Endogeny Biology Pharmacology 030226 pharmacology & pharmacy Models Biological law.invention 03 medical and health sciences 0302 clinical medicine Pharmacokinetics law New chemical entity Drug Discovery Cytochrome P-450 CYP3A Humans Pharmacology (medical) Drug Interactions General Pharmacology Toxicology and Pharmaceutics Clinical pharmacology Clinical study design Cytochrome P-450 CYP3A Inducers Hydroxycholesterols Drug development Liver 030220 oncology & carcinogenesis Biomarker (medicine) Cytochrome P-450 CYP3A Inhibitors Biomarkers |
| Zdroj: | Drug metabolism reviews. 49(1) |
| ISSN: | 1097-9883 |
| Popis: | A key goal in the clinical development of a new molecular entity is to quickly identify whether it has the potential for drug-drug interactions. In particular, confirmation of in vitro data in the early stage of clinical development would facilitate the decision making and inform future clinical pharmacology study designs. Plasma 4β-hydroxycholesterol (4β-HC) is considered as an emerging endogenous biomarker for cytochrome P450 3A (CYP3A), one of the major drug metabolizing enzymes. Although there are increasing reports of the use of 4β-HC in academic- and industry-sponsored clinical studies, a thorough review, summary and consideration of the advantages and challenges of using 4β-HC to evaluate changes in CYP3A activity has not been attempted. Herein, we review the biology of 4β-HC, its response to treatment with CYP3A inducers, inhibitors and mixed inducer/inhibitors in healthy volunteers and patients, the association of 4β-HC with other probes of CYP3A activity (e.g. midazolam, urinary cortisol ratios), and present predictive pharmacokinetic models. We provide recommendations for studying hepatic CYP3A activity in clinical pharmacology studies utilizing 4β-HC at different stages of drug development. |
| Databáze: | OpenAIRE |
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