SLCO1B1 Phenotype and CYP3A5 Polymorphism Significantly Affect Atorvastatin Bioavailability

Abstract

Atorvastatin, prescribed for the treatment of hypercholesterolemia, demonstrated overwhelming benefits in reducing cardiovascular morbidity and mortality. However, many patients discontinue therapy due to adverse reactions, especially myopathy. The Dutch Pharmacogenetics Working Group (DPWG) recommends an alternative agent to atorvastatin and simvastatin or a dose adjustment depending on other risk factors for statin-induced myopathy in SLCO1B1 rs4149056 CC or TC carriers. In contrast, the Clinical Pharmacogenetics Implementation Consortium (CPIC) published their guideline on simvastatin, but not on atorvastatin. In this work, we aimed to demonstrate the effect of SLCO1B1 phenotype and other variants (e.g., in CYP3A4/5, UGT enzymes or SLC transporters) on atorvastatin pharmacokinetics. For this purpose, a candidate-gene pharmacogenetic study was proposed. The study population comprised 156 healthy volunteers enrolled in atorvastatin bioequivalence clinical trials. The genotyping strategy comprised a total of 60 variants in 15 genes. Women showed higher exposure to atorvastatin compared to men (p = 0.001), however this difference disappeared after dose/weight (DW) correction. The most relevant pharmacogenetic differences were the following: AUC/DW and Cmax /DW based on (a) SLCO1B1 phenotype (p < 0.001 for both) and (b) CYP3A5*3 (p = 0.004 and 0.018, respectively). As secondary findings: SLC22A1 *2/*2 genotype was related to higher Cmax/DW (ANOVA p = 0.030) and SLC22A1 *1/*5 genotype was associated with higher Vd/F (ANOVA p = 0.032) compared to SLC22A1 *1/*1, respectively. Finally, UGT2B7 rs7439366 *1/*1 genotype was associated with higher tmax as compared with the *1/*3 genotype (ANOVA p = 0.024). Based on our results, we suggest that SLCO1B1 is the best predictor for atorvastatin pharmacokinetic variability and that prescription should be adjusted based on it. We suggest that the CPIC should include atorvastatin in their statin-SLCO1B1 guidelines. Interesting and novel results were observed based on CYP3A5 genotype, which should be confirmed with further studies.

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

“…The SLCO1B1 *5 (c. 521T >C, p.V174A, rs4149056) variant has been associated with a 221 % higher systemic exposure to simvastatin acid in carriers of the 521CC genotypes than in the wild-type carriers ( 521TT ). Although to a lesser extent, the relevance of this polymorphism was confirmed for other statins ( 85 ) as well, except for fluvastatin ( 100 ). Atorvastatin AUC increased 145 % in 521CC carriers ( 100 ).…”

“…ABCB1 polymorphisms rs1128503 (1236C>T), rs2032582 (2677G>T/A), and rs1045642 (3435C>T) have been shown to markedly affect atorvastatin area under the plasma concentration-time curve (AUC) ( 38 ). However, a recently published study did not establish an association between ABCB1 polymorphisms and the bioavailability of atorvastatin ( 85 ).…”

PriME-PGx: La Princesa University Hospital Multidisciplinary Initiative for the Implementation of Pharmacogenetics

“…Thanks to the availability of these data (i.e., the outcomes of the clinical trials) and the informed consent of the healthy volunteers, a valuable source of information is available for pharmacogenetic research. In the last decade, our group contributed to the expansion of available pharmacogenetic knowledge with numerous publications [36,37,[41][42][43][44][45][46][47].…”

CYP3A5*3 and SLCO1B1 c.521T>C Polymorphisms Influence the Pharmacokinetics of Atorvastatin and 2-Hydroxy Atorvastatin

“…For example, statins can cause myopathy and even rhabdomyolysis, which is a rare adverse effect in certain patients [ 1 , 3 , 4 ]. This toxicity is often associated with increased plasma concentrations of statins caused by drug interactions or hereditary differences in statin pharmacokinetics, and this includes the effect of interindividual variability of enzymatic (e.g., CYP3A5) and transporter (e.g., SLCO1B1) activities caused by SNPs responsible for atorvastatin [ 3 , 5 , 6 ].…”