SLCO1B1 Phenotype and CYP3A5 Polymorphism Significantly Affect Atorvastatin Bioavailability

Journal of Personalized Medicine

Dolores Ochoa¹  Manuel Román²  Samuel Martín-Vílchez²  Marcos Navares-Gómez³  Pablo Zubiaur³  Gonzalo Villapalos-García³  Francisco Abad-Santos³  Gina Mejía-Abril⁴  MariaDolores Benedicto⁵ 

[1] Clinical Pharmacology Department, La Princesa University Hospital, 28006 Madrid, Spain;Clinical Trials Unit of La Princesa University Hospital (UECHUP), La Princesa University Hospital Research Institute, 28006 Madrid, Spain;Pharmacogenetics Unit, Clinical Pharmacology Department, La Princesa University Hospital Research Institute, 28006 Madrid, Spain;Spanish Clinical Research Network (SCReN), La Princesa University Hospital Research Institute, 28006 Madrid, Spain;Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain;

关键词: atorvastatin;    pharmacogenetics;    SLCO1B1;    precision medicine;   

DOI  :  10.3390/jpm11030204

来源: DOAJ

【 摘 要 】

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 C_max /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 C_max/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 t_max 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.

【 授权许可】

Unknown