Different Effects of SLCO1B1 Polymorphism on the Pharmacokinetics of Atorvastatin and Rosuvastatin

Pasanen, Marja K.; Fredrikson, Hanna; Neuvonen, Pertti J.; Niemi, Mikko

doi:10.1038/sj.clpt.6100220

Cited by 384 publications

(345 citation statements)

References 51 publications

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“…In agreement with this are findings showing that genetic variants of OATP1B1 are not predictive for atorvastatin-associated myopathic side effects [15]. It should be noted at this point that in healthy volunteers, the OATP1B1 polymorphisms exerted a more pronounced effect on pharmacokinetic parameters of the atorvastatin acid levels compared with the less lipophilic rosuvastatin [32]. In addition, Lau et al [33] suggested …”

Section: Discussionsupporting

confidence: 73%

Function-impairing polymorphisms of the hepatic uptake transporter SLCO1B1 modify the therapeutic efficacy of statins in a population-based cohort

Schwabedissen

Albers²,

Baumeister³

et al. 2015

Pharmacogenetics and Genomics

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Background The efficacy of statins, which are used commonly in primary and secondary prevention of cardiovascular diseases, shows a wide range of interindividual variability. Genetic variants of OATP1B1, a hepatic uptake transporter, can modify access of statins to its therapeutic target, thereby potentially altering drug efficacy. We studied the impact of genetic variants of OATP1B1 on the lipid-lowering efficacy of statins in a population-based setting. Materials and methodsThe basis of the analysis was the Study of Health in Pomerania, a cohort of 2732 men and women aged 20-81 years. Included in the statistical analysis to evaluate the impact of OATP1B1 on therapeutic efficacy of statins were 214 individuals diagnosed with dyslipidaemia during initial recruitment and receiving statins during the 5-year follow-up.Results Analysing the impact of the OATP1B1 genotype, we observed a trend for lower statin-induced total cholesterol reduction in carriers of the SLCO1B1 512C variant. Restricting the analysis to patients receiving simvastatin, pravastatin, lovastatin and fluvastatin indicated a statistically significant association of the OATP1B1 genotype on lipid parameters at the 5-year follow-up. No such effect was observed for atorvastatin. Calculation of achievement of treatment goals according to the NCEP-ATPIII guidelines showed a lower rate of successful treatment when harbouring the mutant allele for patients taking simvastatin (46.7 vs. 73.9%). A similar trend was observed for pravastatin (34.4 vs. 70.4%).Conclusion Genetic variants of OATP1B1 leading to impaired hepatic uptake of statins translated into reduced drug efficacy in a population-based cohort.

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Section: Discussionsupporting

confidence: 73%

Function-impairing polymorphisms of the hepatic uptake transporter SLCO1B1 modify the therapeutic efficacy of statins in a population-based cohort

Schwabedissen

Albers²,

Baumeister³

et al. 2015

Pharmacogenetics and Genomics

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“…The effects of these two polymorphisms on atorvastatin pharmacokinetics have been robustly identified in Caucasian populations [14,15] and were also recently illustrated in Japanese subjects [16]. It can be hypothesised that the lack of effect in the current work may be due to the small sample size and the complete absence of homozygous variant individuals with respect to these SNPs (Table 2).…”

Section: Discussionmentioning

confidence: 69%

“…For the purpose of this work, all studied participants were retrospectively genotyped for 18 genetic polymorphisms located in 7 different genes. More specifically 3, 3, 1, 1, 7, 2 and 1 polymorphisms were genotyped in the ABCB1, ABCG2, CYP3A4, CYP3A5, SLCO1B1, SLCO2B1 and PPARA genes respectively, as previous literature suggests that all these genes might be implicated in atorvastatin disposition [14,15,[22][23][24][25][26]. The distribution of these variants in the studied population is reported in Table 2.…”

Section: Description Of the Available Data For Model Developmentmentioning

confidence: 99%

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Modelling of atorvastatin pharmacokinetics and the identification of the effect of a BCRP polymorphism in the Japanese population

Tsamandouras

Guo

Wendling

et al. 2017

Pharmacogenetics and Genomics

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Aim(s): Ethnicity has a modulating role in atorvastatin pharmacokinetics, with Asian subjects reported to have higher exposure compared to Caucasians. Therefore, it is difficult to safely extrapolate atorvastatin pharmacokinetic data and models across ethnic groups. This work aims to develop a population pharmacokinetic model for atorvastatin and its pharmacologically active metabolites specifically for the Japanese population. Subsequently it is aimed to identify genetic polymorphisms affecting atorvastatin pharmacokinetics in this population. Methods:Atorvastatin acid and o-OH-atorvastatin acid plasma concentrations, clinical/ demographic characteristics and genotypes for 18 genetic polymorphisms (3, 3, 1, 1, 7, 2 and 1 in the ABCB1, ABCG2, CYP3A4, CYP3A5, SLCO1B1, SLCO2B1 and PPARA genes respectively) were collected from 27 Japanese individuals (taking 10mg atorvastatin once daily) and analysed using a population pharmacokinetics modelling approach. Results:The developed population pharmacokinetic model (one-compartment for atorvastatin acid linked through metabolite formation to an additional compartment describing the disposition of o-OH-atorvastatin acid) accurately described the observed data and the associated population variability. Our analysis suggested that subjects carrying one variant allele for the rs2622604 polymorphism (ABCG2) exhibit a 55% (95%CI: 16%-131%) increase in atorvastatin oral bioavailability relatively to the value in individuals without the variant allele. Conclusion:The current work reports the identification in the Japanese population of a BCRP polymorphism, not previously associated with the pharmacokinetics of any statin, that substantially increases atorvastatin acid and o-OH-atorvastatin acid exposure. The developed model may be of clinical importance in order to guide dosing recommendations tailored specifically for the Japanese.

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“…При изучении фармакокинетики аторвастатина Pasanen MK, et al было установлено, что гомозизоты по аллелю С демонстрируют на 144% (р<0,001) и 61% (р=0,049) большую площадь под кри-вой концентрация-время, чем гомозиготы по аллелю Т и гетерозиготы, соответственно [8]. У носителей генотипа ТТ отмечен статистически значимо более выраженный регресс уровней общего холестерина и липопротеидов низкой плотности (ЛПНП) на фоне лечения аторвастатином по сравнению с носителями генотипов СТ и СС, в то время как разницы между двумя последними не обнаружено [9].…”

Section: фармакотерапия при инфаркте миокарда: вклад генетических факunclassified

Conservative Therapy in Myocardial Infarction: The Impact of Genetic Factors

Солодун¹

2016

Russ J Cardiol

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Different Effects of SLCO1B1 Polymorphism on the Pharmacokinetics of Atorvastatin and Rosuvastatin

Cited by 384 publications

References 51 publications

Function-impairing polymorphisms of the hepatic uptake transporter SLCO1B1 modify the therapeutic efficacy of statins in a population-based cohort

Function-impairing polymorphisms of the hepatic uptake transporter SLCO1B1 modify the therapeutic efficacy of statins in a population-based cohort

Modelling of atorvastatin pharmacokinetics and the identification of the effect of a BCRP polymorphism in the Japanese population

Conservative Therapy in Myocardial Infarction: The Impact of Genetic Factors

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