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


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.


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.


CONCLUSIONS
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.
Department of Epidemiology, Erasmus MC, 3000 CA Rotterdam, the Netherlands.
Matthijs L
ML
Becker
Loes E
LE
Visser
Ron H N
RH
van Schaik
Albert
A
Hofman
André G
AG
Uitterlinden
Bruno H Ch
BH
Stricker
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000069059:Atorvastatin; D002784:Cholesterol / Q000097:blood; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D016208:Databases, Factual; D005260:Female; D005838:Genotype; D006538:Heptanoic Acids / Q000008:administration & dosage* / Q000097:blood / Q000627:therapeutic use; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011758:Pyrroles / Q000008:administration & dosage* / Q000097:blood / Q000627:therapeutic use; D012737:Sex Factors; D019821:Simvastatin / Q000008:administration & dosage* / Q000097:blood / Q000627:therapeutic use
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D002784:Cholesterol; D000069059:Atorvastatin; D019821:Simvastatin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human