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Influence of genetic variation in CYP3A4 and ABCB1 on dose decrease or switching during simvastatin and atorvastatin therapy.

Authors :
Becker ML
Visser LE
van Schaik RH
Hofman A
Uitterlinden AG
Stricker BH
Source :
Pharmacoepidemiology and drug safety [Pharmacoepidemiol Drug Saf] 2010 Jan; Vol. 19 (1), pp. 75-81.
Publication Year :
2010

Abstract

Purpose: Simvastatin and atorvastatin are metabolized by the CYP3A4 enzyme and transported by the ABCB1 transporter. We studied whether the polymorphism CYP3A4*1B and the polymorphisms C1236T, G2677A/T and C3435T in the ABCB1 gene were associated with a decrease of the prescribed dose or a switch to another cholesterol lowering drug during simvastatin and atorvastatin therapy. These events may indicate that statin plasma levels were too high and resulted in an adverse drug reaction or a too strong reduction in cholesterol level.<br />Methods: We identified 1239 incident simvastatin and atorvastatin users in the Rotterdam Study, a population-based cohort study. Associations between the polymorphisms in the CYP3A4 and ABCB1 gene and the time to a decrease in dose or a switch to another cholesterol lowering drug were studied using Cox proportional hazards.<br />Results: Simvastatin and atorvastatin users with the CYP3A4*1B variant G allele had a lower risk (HR 0.46; 95%CI 0.24-0.90) for these events than users with the wild-type AA genotype. No significant associations were found for the ABCB1 polymorphisms. The association with the CYP3A4*1B polymorphism was found in women (HR 0.33; 95%CI 0.12-0.89) and was non-significant in men (HR 0.69 95%CI 0.28-1.70). This association was stronger in patients with the ABCB1 3435T variant allele versus the G allele.<br />Conclusion: In simvastatin and atorvastatin users, the CYP3A4*1B G allele is associated with a lower risk of elevated statin plasma levels, particularly in women and in users with the ABCB1 3435T variant allele.

Details

Language :
English
ISSN :
1099-1557
Volume :
19
Issue :
1
Database :
MEDLINE
Journal :
Pharmacoepidemiology and drug safety
Publication Type :
Academic Journal
Accession number :
19802823
Full Text :
https://doi.org/10.1002/pds.1866