Effect of the ugt1a3*2 haplotype on pharmacokinetics and pharmacodynamics of atorvastatin in patients with coronary heart disease

Background Atorvastatin reduces the risk of atherosclerotic cardiovascular disease but exhibits wide interindividual variability in efficacy and adverse effects, possibly due to genetic predispositions. The SLCO1B1*5 variant causes higher systemic exposure to atorvastatin, and has been associated with increased risk of muscular side effects. The UGT1A3*2 haplotype potentially relate to poorer cholesterol response and increased risk of muscle toxicity by skewing the metabolism towards increased lactonization of atorvastatin metabolites. Purpose To explore the relationship between the UGT1A3*2 haplotype and the pharmacokinetics and pharmacodynamics of atorvastatin in patients with coronary heart disease. Methods We used data from the MUSE study, a double-blinded crossover trial in patients with coronary heart disease. The intervention group with statin-associated muscle symptoms (SAMS, n=70) underwent two 7-week periods with atorvastatin 40 mg and placebo. The control group with no history of SAMS (n=39) received atorvastatin 40 mg during an open-label 7-week period. Blood samples were collected 24h after atorvastatin administration, at the end of each period. We determined pharmacogenetic variants with a multiplex-PCR MALDI-TOF assay. Atorvastatin, its main metabolites, and mevalonate, were quantified with liquid chromatography mass spectrometry. Results Mean age was 64 years and 32% were females. UGT1A3*2 was present in 54% of patients, and the SLCO1B1*5, CYP3A4*22 and CYP3A7*1C variants were present in 29%, 8.3% and 13% (Table 1). In the SAMS group, atorvastatin versus placebo produced mean changes in mevalonate -34 ± 24%, LDL-C -47 ± 19%, and CK +10 ± 33%. In adjusted analysis, SLCO1B1*5 was consistently associated with higher concentrations of atorvastatin and in both acid and lactone form (Table 2). The UGT1A3*2 haplotype was associated with higher levels of hydroxylated atorvastatin and its metabolites. The effects of CYP3A4*22 and CYP3A7*1C were selective towards the non-hydroxylated atorvastatin lactone and 4-hydroxylated atorvastatin lactone, respectively. Regression analysis indicated a more pronounced reduction in mevalonate, a response marker of HMG-CoA reductase inhibition among carriers of UGT1A3*2 whereas none of the examined variants predicted LDL-C response. Unexpectedly, SLCO1B1*5 and CYP3A7*1C were associated with an atorvastatin-related decrease in CK. Conclusions UGT1A3*2 was observed in approximately half of the patients with coronary heart disease and is associated with higher concentrations of hydroxylated atorvastatin metabolites. This haplotype should be considered together with SLCO1B1*5 when predicting effects related to systemic exposure. The results indicate that UGT1A3*2 may have indirect impact on the pharmacodynamics of atorvastatin while further studies are needed to clarify clinical implications for LDL-C lowering and muscle safety.For image description, please refer to the figure legend and surrounding text. For image description, please refer to the figure legend and surrounding text.