CYP3A induction and inhibition by different antiretroviral regimens reflected by changes in plasma 4 beta-hydroxycholesterol levels
(2008) In European Journal of Clinical Pharmacology 64(8). p.775-781- Abstract
- Objective and methods A member of the major human cytochrome P450 superfamily of hemoproteins, CYP3A4/5, converts cholesterol into 4 beta-hydroxycholesterol. We studied plasma 4 beta-hydroxycholesterol levels prior to and 4 weeks after initiating antiretroviral therapy that included efavirenz, ritonavir-boosted atazanavir or ritonavir-boosted lopinavir with the aim of exploring the usefulness of plasma 4 beta-hydroxycholesterol levels as an endogenous biomarker of CYP3A activity. Efavirenz is an inducer of CYP3A, whereas the ritonavir-boosted regimens are net inhibitors of CYP3A. Results In patients treated with efavirenz, the median plasma 4 beta-hydroxycholesterol level increased by 46 ng/mL (p=0.004; n=11). In contast, patients given... (More)
- Objective and methods A member of the major human cytochrome P450 superfamily of hemoproteins, CYP3A4/5, converts cholesterol into 4 beta-hydroxycholesterol. We studied plasma 4 beta-hydroxycholesterol levels prior to and 4 weeks after initiating antiretroviral therapy that included efavirenz, ritonavir-boosted atazanavir or ritonavir-boosted lopinavir with the aim of exploring the usefulness of plasma 4 beta-hydroxycholesterol levels as an endogenous biomarker of CYP3A activity. Efavirenz is an inducer of CYP3A, whereas the ritonavir-boosted regimens are net inhibitors of CYP3A. Results In patients treated with efavirenz, the median plasma 4 beta-hydroxycholesterol level increased by 46 ng/mL (p=0.004; n=11). In contast, patients given ritonavir-boosted atazanavir showed a median decrease in plasma 4 beta-hydroxycholesterol of -9.4 ng/mL (p=0.0003; n=22), and those given ritonavir-boosted lopinavir showed a median change from baseline of -5.8 ng/mL (p=0.38; n=19). There were significant between-group differences in the effects of antiretroviral treatment on plasma 4 beta-hydroxycholesterol levels (p < 0.0001). Conclusion Changes in plasma 4 beta-hydroxycholesterol following the initiation of efavirenz- or atazanavir/ritonavir-based antiretroviral therapy reflected the respective net increase and decrease of CYP3A activity of these regimens. The plasma 4 beta-hydroxycholesterol level did not indicate a net CYP3A inhibition in the lopinavir/ritonavir arm, possibly because of concomitant enzyme induction. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1191071
- author
- Josephson, F ; Bertilsson, L ; Bottiger, Y ; Flamholc, Leo LU ; Gisslen, M ; Ormaasen, V ; Sonnerborg, A and Diczfalusy, U
- organization
- publishing date
- 2008
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- 4 beta-hydroxycholesterol, CYP3A, antiretroviral, biomarker, inhibition, induction
- in
- European Journal of Clinical Pharmacology
- volume
- 64
- issue
- 8
- pages
- 775 - 781
- publisher
- Springer
- external identifiers
-
- wos:000256927900004
- scopus:45849151673
- pmid:18458892
- ISSN
- 1432-1041
- DOI
- 10.1007/s00228-008-0492-8
- language
- English
- LU publication?
- yes
- id
- a7a2683f-3284-46ff-a166-a36ffbe43342 (old id 1191071)
- date added to LUP
- 2016-04-01 14:37:13
- date last changed
- 2022-01-28 01:36:04
@article{a7a2683f-3284-46ff-a166-a36ffbe43342,
abstract = {{Objective and methods A member of the major human cytochrome P450 superfamily of hemoproteins, CYP3A4/5, converts cholesterol into 4 beta-hydroxycholesterol. We studied plasma 4 beta-hydroxycholesterol levels prior to and 4 weeks after initiating antiretroviral therapy that included efavirenz, ritonavir-boosted atazanavir or ritonavir-boosted lopinavir with the aim of exploring the usefulness of plasma 4 beta-hydroxycholesterol levels as an endogenous biomarker of CYP3A activity. Efavirenz is an inducer of CYP3A, whereas the ritonavir-boosted regimens are net inhibitors of CYP3A. Results In patients treated with efavirenz, the median plasma 4 beta-hydroxycholesterol level increased by 46 ng/mL (p=0.004; n=11). In contast, patients given ritonavir-boosted atazanavir showed a median decrease in plasma 4 beta-hydroxycholesterol of -9.4 ng/mL (p=0.0003; n=22), and those given ritonavir-boosted lopinavir showed a median change from baseline of -5.8 ng/mL (p=0.38; n=19). There were significant between-group differences in the effects of antiretroviral treatment on plasma 4 beta-hydroxycholesterol levels (p < 0.0001). Conclusion Changes in plasma 4 beta-hydroxycholesterol following the initiation of efavirenz- or atazanavir/ritonavir-based antiretroviral therapy reflected the respective net increase and decrease of CYP3A activity of these regimens. The plasma 4 beta-hydroxycholesterol level did not indicate a net CYP3A inhibition in the lopinavir/ritonavir arm, possibly because of concomitant enzyme induction.}},
author = {{Josephson, F and Bertilsson, L and Bottiger, Y and Flamholc, Leo and Gisslen, M and Ormaasen, V and Sonnerborg, A and Diczfalusy, U}},
issn = {{1432-1041}},
keywords = {{4 beta-hydroxycholesterol; CYP3A; antiretroviral; biomarker; inhibition; induction}},
language = {{eng}},
number = {{8}},
pages = {{775--781}},
publisher = {{Springer}},
series = {{European Journal of Clinical Pharmacology}},
title = {{CYP3A induction and inhibition by different antiretroviral regimens reflected by changes in plasma 4 beta-hydroxycholesterol levels}},
url = {{http://dx.doi.org/10.1007/s00228-008-0492-8}},
doi = {{10.1007/s00228-008-0492-8}},
volume = {{64}},
year = {{2008}},
}