Influence of OATP1B1 and BCRP polymorphisms on the pharmacokinetics and pharmacodynamics of rosuvastatin in elderly and young Korean subjects

Jae-Yong Chung,Kyung-Sang Yu,Seo Hyun Yoon,In-Jin Jang,Yun Kim,Yewon Choi,Seonghae Yoon,Joo-Youn Cho

doi:10.1038/s41598-019-55562-4

Jae-Yong Chung, Kyung-Sang Yu + Show 6 more

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https://doi.org/10.1038/s41598-019-55562-4

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Abstract

A lack of information regarding whether genetic polymorphisms of SLCO1B1 and ABCG2 affect the pharmacokinetics (PKs)/pharmacodynamics (PDs) of rosuvastatin in elderly subjects prevents optimal individualized pharmacotherapy of rosuvastatin in clinical settings. This study aimed to investigate the effect of age and genetic polymorphisms and possible differences in genetic effects on the PKs/PDs of rosuvastatin between elderly and young subjects. Two separate clinical studies designed as open-label, one-sequence studies with multiple-dose administration for elderly (n = 20) and young (n = 32) subjects were conducted. All subjects received 20 mg of rosuvastatin once daily for 21 days. The exposure to rosuvastatin, characterized by the area under the time curve (AUC), increased by 23% in the elderly subjects compared with that of young subjects, which was not significant. When compared to the subjects with breast cancer resistance protein (BCRP) normal function, the exposure to rosuvastatin increased by 44% in young subjects (p = 0.0021) with BCRP intermediate function (IF) and by 35% and 59% (p > 0.05 for both) in elderly subjects with BCRP IF and low function, respectively. SLCO1B1 521T > C was also partially associated with a higher AUC of rosuvastatin in young subjects and a less pronounced increasing trend in elderly subjects (p > 0.05 for both). The lipid-lowering effect of rosuvastatin was less pronounced in the elderly subjects than in the young subjects, and genetic polymorphisms of neither SLCO1B1 nor ABCG2 significantly affected the PDs of rosuvastatin. The ABCG2 421C > A polymorphism was associated with the PKs of rosuvastatin and was identified as a more important determinant than the SLCO1B1 521T > C polymorphism in both elderly and young subjects.

Highlights

Rosuvastatin is one of the most hydrophilic statins (3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitors) used for the treatment of hyperlipidemia[1]
When we only considered the reduced function of OATP1B1 (OATP1B1/breast cancer resistance protein (BCRP) groups: normal function (NF)/NF vs. intermediate function (IF)/NF vs. LF/NF, NF/IF vs. IF/IF), the exposure to rosuvastatin remained similar in the elderly subjects, whereas exposure increased in the young subjects (p > 0.05 for both: NF/NF vs. IF/NF, 19%; NF/NF vs. LF/NF, 66%) [Fig. 2(a,b) and Table 2]
We investigated the influence of age and polymorphisms in SLCO1B1 and ABCG2 on the PKs/PDs of rosuvastatin in healthy elderly and young subjects

Summary

Introduction

Rosuvastatin is one of the most hydrophilic statins (3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitors) used for the treatment of hyperlipidemia[1]. Drug transporters are considered to be important determinants of rosuvastatin pharmacokinetic/pharmacodynamic (PK/PD) profiles, and genetic polymorphisms of OATP1B1 and BCRP are known to be associated with interindividual variability in the PKs/PDs of rosuvastatin[14,15,16]. Through its effect on altered rosuvastatin absorption, the 421C > A single-nucleotide polymorphism (SNP) in ABCG2 appears to be a major genetic factor associated with the PKs of rosuvastatin, with higher exposure compared with that in noncarriers of this allele[12]. There is currently a lack of information regarding whether genetic polymorphisms of OATP1B1 and BCRP affect the PKs/PDs of rosuvastatin in elderly subjects. This study was conducted to determine whether genetic polymorphisms of OATP1B1 and BCRP influence PKs/PDs after multiple-dose administration of rosuvastatin in elderly subjects and to compare the results with those of young subjects

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