Genetic Variation in the UGT1A Locus is Associated with Simvastatin Efficacy in a Clinical Practice Setting

Abstract

Aim Simvastatin is a lactone prodrug that exists in equilibrium with its active hydroxyacid through a process mediated by UGT1A enzymes. The UGT1A locus has been associated with simvastatin response and disposition in humans. Therefore, we fine-mapped the UGT1A locus to identify genetic variations contributing to simvastatin disposition and response variability. Methods Using de-identified electronic medical records linked to a DNA biobank, we extracted information about dose and low-density lipo protein cholesterol (LDL-C) concentrations for patients who received more than two different doses of simvastatin. Pharmacodynamic measures of simvastatin potency and efficacy were calculated from dose–response curves (E0 = baseline LDL-C, ED50 = dose yielding 50% maximum response, and Emax = maximum decrease in LDL-C) in 1100 patients. We selected 153 polymorphisms in UGT1A1 and UGT1A3 for genotyping and conducted genotype–phenotype associations using a prespecified additive model. Results Two variants in UGT1A1 (rs2003569 and rs12052787) were associated with Emax (p = 0.0059 and 0.031, respectively; for rs2003569 the mean Emax was 59.3 ± 23.0, 62.0 ± 22.4, and 69.7 ± 24.8 mg/dl, for patients with 0, 1 or 2 copies of the minor A allele, respectively). When stratified by race, the difference in response was greater in African–Americans than in European Americans. Rs2003569 was also negatively associated with total serum bilirubin levels (p = 7.85 × 10−5). Four rare SNPs were nominally associated with E0 and ED50. Conclusion We identified a UGT1A1 promoter variant (rs2003569) associated with simvastatin efficacy.

Effects of Simvastatin on Pharmacokinetics and Anticoagulant Effects of Dabigatran in Healthy Subjects

“…It has been reported that simvastatin acid undergoes glucuronidation in human microsomes and forms its lactone form [ 30 ]. In addition, efficacy of simvastatin has been found to be associated with single nucleotide polymorphisms in UGT1A1 [ 31 ]. However, there is no confirmatory evidence of whether simvastatin can induce UGT.…”

Drug-drug-gene interactions as mediators of adverse drug reactions to diclofenac and statins: a case report and literature review

“…Statins are the first-line treatment for hypercholesterolemia in both primary and secondary prevention of cardiovascular disease ( 26 ). Simvastatin is a prodrug, administered as inactive lactone and then converted to open hydroxy acid form ( 27 ). Atorvastatin is orally administered in active acid form ( 28 ).…”

“…Both undergo extensive first-pass metabolism in the intestine and liver ( Figure 4 ), mediated primarily by CYP3A4 with a minor contribution of CYP2C9 and CYP3A5 ( 29 , 30 , 31 , 32 ). The main enzymes involved in statin glucuronidation are UGTs (1A1, 1A3, 2B7) ( 27 , 33 , 34 , 35 , 36 , 37 ).…”

Effects of Silymarin on the In Vivo Pharmacokinetics of Simvastatin and Its Active Metabolite in Rats

“…Studies also indicated that SV can be hydrolyzed to SVA by esterases, paraoxonases or through chemical approaches [43,44]. UGTs, especially UGT1A1 and UGT1A3, were also found as SV metabolizing proteins which catalyze the formation of glucuronide conjugates of SVA and its reversible conversion to SV [45].…”