Studies on 4 β -hydroxycholesterol as an endogenous biomarker for CYP3A4 phenotype
Appears in the following Collection
- Farmasøytisk institutt 
AbstractThere is extensive interindividual variability in drug response and tolerability. One of the major reasons for this is differences in drug metabolism, which may reflect pharmacogenetic variability and/or environmental factors, such as age and drug-drug interactions. Cytochrome P450 3A4 (CYP3A4) is the most important enzyme in drug metabolism, but its phenotype is not determined by pharmacogenetic differences. Thus there is a great interest in identifying practical non-genetic measures as potential CYP3A4 biomarkers. 4β-Hydroxycholesterol (4βOHC) is formed from cholesterol by CYP3A4 and has been proposed as a biomarker for determination of individual patients CYP3A4 activity (phenotype). The overall aim of this thesis was to investigate different aspects of 4β-hydroxycholesterol as a potential biomarker for CYP3A4 phenotype. An initial study of the thesis found a significant correlation between 4βOHC level and daily dose but not steady-state serum concentration of carbamazepine, a potent CYP3A4 inducer. The dose specific induction indicated that 4βOHC level reflects both intestinal and hepatic phenotype, which is considered important for a CYP3A4 biomarker to be robust. A second study investigating the correlation between 4βOHC level and steady-state serum concentration during oral use of the antipsychotic drug quetiapine, a CYP3A4 substrate subjected to extensive presystemic metabolism, showed that 4βOHC level, age and gender explained approximately 30% of the variability in dose-corrected serum concentrations of quetiapine. In addition to supporting a role of intestinal CYP3A4 in biomarker formation, the study supported a potential clinical usefulness of 4βOHC as a biomarker for estimation of individual dose requirements of quetiapine, as well as monitoring of CYP3A4 phenotype during ongoing therapy. However, in a subsequent third study in 22 healthy volunteers who consumed grapefruit juice (GFJ), an intestinal CYP3A4 inhibitor, for three weeks, no significant reduction in cholesterol corrected levels of 4βOHC was observed. This latter finding suggests that intestinal CYP3A4 likely plays a minor role in formation of 4βOHC. In conclusion, the findings of the thesis may support a potential application of 4βOHC as an endogenous biomarker for monitoring of CYP3A4 phenotype in clinical practice, but it is unlikely that it could be used for estimation of individual dose requirements of CYP3A4 substrates without accounting for other factors of importance for the respective drug’s pharmacokinetic variability.
List of papers
|I. Gjestad C, Huynh DK, Haslemo T, Molden E. 4β-hydroxycholesterol correlates with dose but not steady-state concentration of carbamazepine: indication of intestinal CYP3A in biomarker formation? Br J Clin Pharmacol 2016;81(2):269-76. The paper is not available in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.1111/bcp.12833|
|II. Gjestad C, Haslemo T, Andreassen OA, Molden E. 4β-Hydroxycholesterol level significantly correlates with steady-state serum concentration of the CYP3A4 substrate quetiapine in psychiatric patients. Br J Clin Pharmacol 2017;83(11):2398-2405. The paper is not available in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.1111/bcp.13341|
|III. Gjestad C, Hole K, Haslemo T, Diczfalusy U, Molden E. Effect of grapefruit juice intake on serum 4β-hydroxycholesterol levels – an interaction study in healthy volunteers. AAPS J 2019;21(4):58. The paper is not available in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.1208/s12248-019-0330-1|