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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

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

Hukkanen Janne J Puurunen Johanna J Hyötyläinen Tuulia T Savolainen Markku J MJ Ruokonen Aimo A Morin-Papunen Laure L Orešič Matej M Piltonen Terhi T Tapanainen Juha S JS

British journal of clinical pharmacology 20150722 3

<h4>Aims</h4>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).<h4>Methods</h4>In this randomized, double-blind, placebo-controll ...[more]

PMID: 26095142

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Project description:Abstract Study Objective. To assess the effects of the cytochrome P450 (CYP) 3A genotype, CYP3A5, on atorvastatin pharmacokinetics and its interaction with clarithromycin. Design. Prospective, two-phase, randomized-sequence, open-label pharmacokinetic study. Setting. Clinical research center at a teaching hospital. Subjects. Twenty-three healthy volunteers who were screened for genotype: 10 subjects carried the CYP3A5*1 allele (expressors) and 13 subjects did not (nonexpressors). Intervention. In one phase, subjects received a single oral dose of atorvastatin 20 mg. In the other phase, subjects received clarithromycin 500 mg twice/day for 5 days; on day 4 after the morning dose, subjects also received a single oral dose of atorvastatin 20 mg. All subjects participated in both phases of the study, which were separated by at least 14 days. Measurements and Main Results. Pharmacokinetic parameters of both forms of atorvastatin-atorvastatin acid and atorvastatin lactone-were compared between CYP3A5 expressors and nonexpressors, both in the absence and presence of clarithromycin, a strong CYP3A inhibitor. The acid form is pharmacologically active, and the lactone form has been associated with the atorvastatin's muscle-related adverse effects. Atorvastatin acid exposure did not differ significantly between CYP3A5 genotype groups. When subjects had not received clarithromycin pretreatment, the area under the concentration-time curve from time zero extrapolated to infinity (AUC(0-?)) of atorvastatin lactone was 36% higher in nonexpressors than in expressors (median 47.6 ng•hr/ml [interquartile range (IQR) 37.8-64.3 ng•hr/ml] vs 34.9 ng•hr/ml [IQR 21.6-42.2 ng•hr/ml], p=0.038). After clarithromycin pretreatment, changes in the pharmacokinetic parameters of atorvastatin acid and lactone were not significantly different between the nonexpressors versus the expressors; however, the increase in the AUC(0-?) of atorvastatin lactone was 37% greater in expressors than in nonexpressors (geometric mean ± SD 3.59 ± 0.57 vs 2.62 ± 0.35, p=0.049). Conclusion. Our data suggest that the CYP3A5 genotype has minimal effects on the pharmacokinetic parameters of atorvastatin and its interaction with clarithromycin; these effects are unlikely to be clinically significant.

Dataset Information

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

Publications

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

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