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

ABSTRACT: 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 4?-hydroxycholesterol to cholesterol ratio (4?HC : C). METHODS:In this randomized, double-blind, placebo-controlled 6?month study we evaluated the effects of atorvastatin 20?mg?day(-1) (n?=?15) and placebo (n?=?14) on oxysterol concentrations and determined if atorvastatin induces or inhibits CYP3A4 activity as assessed by the 4?HC : C index. The respective 25-hydroxycholesterol and 5?,6?-epoxycholesterol ratios were used as negative controls. RESULTS:Treatment with atorvastatin decreased 4?HC and 5?,6?-epoxycholesterol concentrations by 40% and 23%, respectively. The mean 4?HC : 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 4?HC : 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. CONCLUSIONS:The results establish atorvastatin as an inhibitor of CYP3A4 activity. Furthermore, 4?HC : C is a useful index of CYP3A4 activity, including the conditions with altered cholesterol concentrations.

SUBMITTER: Hukkanen J 

PROVIDER: S-EPMC4574832 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature