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CYP3A induction and inhibition by different antiretroviral regimens reflected by changes in plasma 4 beta-hydroxycholesterol levels

Josephson, F; Bertilsson, L; Bottiger, Y; Flamholc, Leo LU ; Gisslen, M; Ormaasen, V; Sonnerborg, A and Diczfalusy, U (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)
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author
organization
publishing date
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
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
2008-09-08 11:16:30
date last changed
2017-03-05 03:57:21
@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 &lt; 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},
  keyword      = {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},
  volume       = {64},
  year         = {2008},
}