Pharmacokinetics and Genetic Factors of Atorvastatin in Healthy Korean Subjects

Serim Kim; Jong Do Seo; Yeo-Min Yun; Hanah Kim; Tae-Eun Kim; Taeheon Lee; Tae-Rim Lee; Jun Hyung Lee; Eun-Hae Cho; Chang-Seok Ki

doi:10.3389/fgene.2022.836970

Pharmacokinetics and Genetic Factors of Atorvastatin in Healthy Korean Subjects

Front Genet. 2022 May 19:13:836970. doi: 10.3389/fgene.2022.836970. eCollection 2022.

Authors

Serim Kim¹, Jong Do Seo², Yeo-Min Yun^{2

3}, Hanah Kim^{2

3}, Tae-Eun Kim⁴, Taeheon Lee⁵, Tae-Rim Lee⁵, Jun Hyung Lee⁶, Eun-Hae Cho⁵, Chang-Seok Ki⁵

Affiliations

¹ Department of Laboratory Medicine, Shinwon Medical Foundation, Gwangmyeong-si, South Korea.
² Department of Laboratory Medicine, Konkuk University Medical Center, Seoul, South Korea.
³ Department of Laboratory Medicine, Konkuk University School of Medicine, Seoul, South Korea.
⁴ Department of Clinical Pharmacology, Konkuk University Medical Center, Seoul, South Korea.
⁵ GC Genome, Yongin-si, South Korea.
⁶ Department of Laboratory Medicine, GC Labs, Yongin-si, South Korea.

Abstract

Background: Statins are the most popular agents for the primary and secondary prevention of cardiovascular disease; however, the pharmacokinetic parameters and associated genetic factors in the Korean population have not been fully elucidated. This study explored the pharmacokinetic properties of atorvastatin and the association between genetic variations and atorvastatin pharmacokinetics in healthy Korean subjects. Methods: Atorvastatin (80 mg) was administered to 35 healthy Korean volunteers. Plasma levels of atorvastatin and its metabolites were measured sequentially using liquid chromatography-tandem mass spectrometry from 0 to 24 h after atorvastatin administration. Customized next-generation sequencing analysis was performed covering all coding exons of 15 genes, as well as 46 single-nucleotide variants in 29 genes related to statin pharmacokinetics. Results: The mean area under the concentration-time (AUC) and C_max (maximum peak concentration) were 269.0 ng/ml∙h and 84.3 ng/ml, respectively, which were approximately two times higher than those reported in Caucasians. Genetic analysis revealed that eight genetic variants in ABCB1, ABCG2, APOA5, CETP, and CYP7A1 contributed to the AUC of atorvastatin. The atorvastatin AUC_{0-24 h} prediction model was developed based on age and eight genetic variants using multivariate linear regression (adjusted R ² = 0.878, p < 0.0001). Conclusion: This study shows that the pharmacokinetic properties of atorvastatin in Koreans are different from those in Caucasians and that atorvastatin AUC_{0-24 h} could be predicted based on age and eight genetic variants of ABCB1, ABCG2, APOA5, CETP, and CYP7A1.

Keywords: atorvastatin; liquid chromatography-tandem mass spectrometry; next-generation sequencing; pharmacogenetics; pharmacokinetic parameter.