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

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.