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The effect of atorvastatin treatment on serum oxysterol concentrations and cytochrome P450 3A4 activity
University of Oulu, Oulu, Finland; Oulu University Hospital, Oulu, Finland.
University of Oulu, Oulu, Finland; Oulu University Hospital, Oulu, Finland.
Steno Diabetes Center, Gentofte, Denmark.ORCID iD: 0000-0002-4382-4355
University of Oulu, Oulu, Finland; Oulu University Hospital, Oulu, Finland.
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2015 (English)In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 80, no 3, p. 473-479Article in journal (Refereed) Published
Abstract [en]

Aims: Atorvastatin is known to both inhibit and induce the cytochrome P450 3A4 (CYP3A4) enzyme in vitro. Some clinical studies indicate that atorvastatin inhibits CYP3A4 but there are no well-controlled longer term studies that could evaluate the inducing effect of atorvastatin. We aimed to determine if atorvastatin induces or inhibits CYP3A4 activity as measured by the 4β-hydroxycholesterol to cholesterol ratio (4βHC : C).

Methods: In this randomized, double-blind, placebo-controlled 6 month study we evaluated the effects of atorvastatin 20mg day1 (n=15) and placebo (n = 14) on oxysterol concentrations and determined if atorvastatin induces or inhibits CYP3A4 activity as assessed by the 4βHC : C index. The respective 25-hydroxycholesterol and 5α,6α- epoxycholesterol ratios were used as negative controls.

Results: Treatment with atorvastatin decreased 4βHC and 5α,6α-epoxycholesterol concentrations by 40% and 23%, respectively. The mean 4βHC : C ratio decreased by 13% (0.214 ± 0.04 to 0.182 ± 0.04, P = 0.024, 95% confidence interval (CI) of the difference –0.0595, –0.00483) in the atorvastatin group while no significant change occurred in the placebo group. The difference in change of 4βHC : C between study arms was statistically significant (atorvastatin –0.032, placebo 0.0055, P = 0.020, 95% CI of the difference – 0.069, –0.0067). The ratios of 25-hydroxycholesterol and 5α,6α- epoxycholesterol to cholesterol did not change.

Conclusions: The results establish atorvastatin as an inhibitor of CYP3A4 activity.

Furthermore, 4βHC : C is a useful index of CYP3A4 activity, including the

conditions with altered cholesterol concentrations.

Place, publisher, year, edition, pages
Blackwell Publishing, 2015. Vol. 80, no 3, p. 473-479
Keywords [en]
25-hydroxycholesterol, 4β-hydroxycholesterol, 5α, 6α-epoxycholesterol, atorvastatin, desmosterol, pregnane X receptor
National Category
Medical and Health Sciences Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:oru:diva-65676DOI: 10.1111/bcp.12701ISI: 000360371900015PubMedID: 26095142Scopus ID: 2-s2.0-84940453694OAI: oai:DiVA.org:oru-65676DiVA, id: diva2:1189783
Funder
Academy of Finland
Note

Cited By :4; Export Date: 12 March 2018; Article

Funding Agencies:

Duodecim Society of Oulu 

Finnish Medical Foundation 

Sigrid Juselius Foundation 

National Clinical Graduate School 

Research Foundation of Obstetrics and Gynecology 

Oulu University Scholarship Foundation 

North Ostrobothnia Regional Fund of the Finnish Cultural Foundation

Tyyni Tani Foundation of the University of Oulu 

Finnish-Norwegian Medical Foundation 

Available from: 2018-03-12 Created: 2018-03-12 Last updated: 2019-03-04Bibliographically approved

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Hyötyläinen, TuuliaOresic, Matej

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