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

Author(s): Josephson F, Bertilsson L, Bottiger Y, Flamholc L, Gisslen M, Ormaasen V, Sonnerborg A, Diczfalusy U

Affiliation(s): Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden. filip.josephson@karolinska.se

Publication date & source: 2008-08, Eur J Clin Pharmacol., 64(8):775-81. Epub 2008 May 6.

Publication type: Clinical Trial, Phase IV; Comparative Study; Multicenter Study; Randomized Controlled Trial; Research Support, Non-U.S. Gov't

OBJECTIVE AND METHODS: A member of the major human cytochrome P450 superfamily of hemoproteins, CYP3A4/5, converts cholesterol into 4beta-hydroxycholesterol. We studied plasma 4beta-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 4beta-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 4beta-hydroxycholesterol level increased by 46 ng/mL (p = 0.004; n = 11). In contrast, patients given ritonavir-boosted atazanavir showed a median decrease in plasma 4beta-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 4beta-hydroxycholesterol levels (p < 0.0001). CONCLUSION: Changes in plasma 4beta-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 4beta-hydroxycholesterol level did not indicate a net CYP3A inhibition in the lopinavir/ritonavir arm, possibly because of concomitant enzyme induction.

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