The effect of atorvastatin treatment on serum oxysterol concentrations and cytochrome P450 3A4 activity

: Hukkanen J, Puurunen J, Hyotylainen T, Savolainen MJ, Ruokonen A, Morin-Papunen L, Oresic M, Piltonen T, Tapanainen JS

Publisher: WILEY-BLACKWELL

: 2015

: British Journal of Clinical Pharmacology

: BRITISH JOURNAL OF CLINICAL PHARMACOLOGY

: BRIT J CLIN PHARMACO

: 80

: 3

: 473

: 479

: 7

: 0306-5251

DOI: https://doi.org/10.1111/bcp.12701

AimsAtorvastatin 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 4-hydroxycholesterol to cholesterol ratio (4HC : C).MethodsIn this randomized, double-blind, placebo-controlled 6month study we evaluated the effects of atorvastatin 20mgday(-1) (n=15) and placebo (n=14) on oxysterol concentrations and determined if atorvastatin induces or inhibits CYP3A4 activity as assessed by the 4HC : C index. The respective 25-hydroxycholesterol and 5,6-epoxycholesterol ratios were used as negative controls.ResultsTreatment with atorvastatin decreased 4HC and 5,6-epoxycholesterol concentrations by 40% and 23%, respectively. The mean 4HC : C ratio decreased by 13% (0.2140.04 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 4HC : 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 5,6-epoxycholesterol to cholesterol did not change.ConclusionsThe results establish atorvastatin as an inhibitor of CYP3A4 activity. Furthermore, 4HC : C is a useful index of CYP3A4 activity, including the conditions with altered cholesterol concentrations.