Loss of function polymorphisms in SLCO1B1 (c.521T&gt;C, rs4149056) and ABCG2 (c.421C&gt;A, rs2231142) genes are associated with adverse events of rosuvastatin: a case–control study

Merćep, Iveta; Radman, Ivana; Trkulja, Vladimir; Božina, Tamara; Šimičević, Livija; Budimir, Ema; Ganoci, Lana; Božina, Nada

doi:10.1007/s00228-021-03233-7

Cited by 12 publications

(6 citation statements)

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“…However, the risk of muscle toxicity may increase in the event of DDIs that lead to the inhibition of statin metabolizing enzymes and transporters (Abd and Jacobson, 2011). Similarly, a decreased function genetic variant of the ABCG2 gene encoding BCRP, (rs2231142, c.421C>A), has been associated with atorvastatin-, fluvastatin-, and rosuvastatin-induced musculoskeletal and hepatic adverse effects (Merćep et al, 2022;Miroševic Skvrce et al, 2013;Mirošević Skvrce et al, 2015). On the other hand, TKIs may cause severe adverse effects related to cardiotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Novel inhibitors of breast cancer resistance protein (BCRP, ABCG2) among marketed drugs

Deng

Sjöstedt

Santo

et al. 2023

European Journal of Pharmaceutical Sciences

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Section: Discussionmentioning

confidence: 99%

Novel inhibitors of breast cancer resistance protein (BCRP, ABCG2) among marketed drugs

Deng

Sjöstedt

Santo

et al. 2023

European Journal of Pharmaceutical Sciences

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“…For example, homozygosity for the reduced function c.521 T > C (rs4149056, p.Val174Ala) single nucleotide variation (SNV) in SLCO1B1 is associated with a 1.8–2.7‐fold increase in rosuvastatin peak plasma concentration ( C max ) and a 1.6–2.2‐fold increase in rosuvastatin AUC 21,22 . The c.521 T > C SNV is also associated with a potentially increased risk of rosuvastatin‐associated myotoxicity 23,24 …”

Section: Introductionmentioning

confidence: 99%

“…21,22 The c.521 T > C SNV is also associated with a potentially increased risk of rosuvastatin-associated myotoxicity. 23,24 Understanding of genetic variability in rosuvastatin pharmacokinetics has so far been based on targeted candidate gene studies, and genetic variants affecting rosuvastatin pharmacokinetics may therefore still be unidentified. Therefore, we considered it important to conduct a comprehensive pharmacogenetic study on rosuvastatin pharmacokinetics.…”

Section: Introductionmentioning

confidence: 99%

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A comprehensive pharmacogenomic study indicates roles for SLCO1B1, ABCG2 and SLCO2B1 in rosuvastatin pharmacokinetics

Lehtisalo

Taskinen

Tarkiainen

et al. 2022

Brit J Clinical Pharma

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Aims The aim was to comprehensively investigate the effects of genetic variability on the pharmacokinetics of rosuvastatin. Methods We conducted a genome‐wide association study and candidate gene analyses of single dose rosuvastatin pharmacokinetics in a prospective study (n = 159) and a cohort of previously published studies (n = 88). Results In a genome‐wide association meta‐analysis of the prospective study and the cohort of previously published studies, the SLCO1B1 c.521 T > C (rs4149056) single nucleotide variation (SNV) associated with increased area under the plasma concentration–time curve (AUC) and peak plasma concentration of rosuvastatin (P = 1.8 × 10−12 and P = 3.2 × 10−15). The candidate gene analysis suggested that the ABCG2 c.421C > A (rs2231142) SNV associates with increased rosuvastatin AUC (P = .0079), while the SLCO1B1 c.388A > G (rs2306283) and SLCO2B1 c.1457C > T (rs2306168) SNVs associate with decreased rosuvastatin AUC (P = .0041 and P = .0076). Based on SLCO1B1 genotypes, we stratified the participants into poor, decreased, normal, increased and highly increased organic anion transporting polypeptide (OATP) 1B1 function groups. The OATP1B1 poor function phenotype associated with 2.1‐fold (90% confidence interval 1.6–2.8, P = 4.69 × 10−5) increased AUC of rosuvastatin, whereas the OATP1B1 highly increased function phenotype associated with a 44% (16–62%; P = .019) decreased rosuvastatin AUC. The ABCG2 c.421A/A genotype associated with 2.2‐fold (1.5–3.0; P = 2.6 × 10−4) increased AUC of rosuvastatin. The SLCO2B1 c.1457C/T genotype associated with 28% decreased rosuvastatin AUC (11–42%; P = .01). Conclusion These data suggest roles for SLCO1B1, ABCG2 and SLCO2B1 in rosuvastatin pharmacokinetics. Poor SLCO1B1 or ABCG2 function genotypes may increase the risk of rosuvastatin‐induced myotoxicity. Reduced doses of rosuvastatin are advisable for patients with these genotypes.

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“…Similarly, Tomlinson et al and Kozhakhmetov et al showed that 421 A allele carriers had greater reductions in LCL-C and total cholesterol in patients treated with rosuvastatin [ 26 , 27 ]. In terms of adverse effects, Merćep et al reported that 421 C>A increased two times higher risks of rosuvastatin-related myotoxicity and hepatotoxicity [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

The Association between ABCG2 421C>A (rs2231142) Polymorphism and Rosuvastatin Pharmacokinetics: A Systematic Review and Meta-Analysis

et al. 2022

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Although several studies have revealed the association between rosuvastatin pharmacokinetics and the ABCG2 421C>A (rs2231142) polymorphism, most studies were conducted with small sample sizes, making it challenging to apply the findings clinically. Therefore, the purpose of this study is to perform a meta-analysis of the relationship between the ABCG2 421C>A polymorphism and rosuvastatin pharmacokinetics. We searched three electronic databases, EMBASE, PubMed, and Web of Science, using search terms related to ABCG2 gene polymorphisms and rosuvastatin. In addition, we reviewed studies published before 12 August 2021, to examine the relationship between the ABCG2 421C>A polymorphism and rosuvastatin pharmacokinetics. To examine the magnitude of the association, the log geometric mean difference (lnGM) and 95% confidence intervals (CIs) were calculated and interpreted as the antilogarithm of a natural logarithm (elnGM). The meta-analysis was performed using Review Manager (version 5.4) and R Studio (version 4.0.2). Subgroup analysis was performed according to race and the types of mean values. Among the 318 identified studies, a total of 8 studies involving 423 patients is included in this meta-analysis. The A allele carriers of ABCG2 421C>A showed 1.5 times higher in both AUC0-∞ (lnGM = 0.43; 95% CI = 0.35‒0.50; p < 0.00001) and Cmax (lnGM = 0.42; 95% CI = 0.33‒0.51; p < 0.00001) than non-carriers, while there was no significant difference in Tmax and half-life. There was no significance in the pharmacokinetic parameters of the subgroups using either ethnicity or mean values. This meta-analysis demonstrates that subjects carrying the A allele of ABCG2 421C>A show significantly increased AUC0-∞ and Cmax values compared to subjects with the CC genotype. Therefore, information about ABCG2 genotypes might be useful for individualized rosuvastatin therapy.

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Loss of function polymorphisms in SLCO1B1 (c.521T>C, rs4149056) and ABCG2 (c.421C>A, rs2231142) genes are associated with adverse events of rosuvastatin: a case–control study

Cited by 12 publications

References 50 publications

Novel inhibitors of breast cancer resistance protein (BCRP, ABCG2) among marketed drugs

Novel inhibitors of breast cancer resistance protein (BCRP, ABCG2) among marketed drugs

A comprehensive pharmacogenomic study indicates roles for SLCO1B1, ABCG2 and SLCO2B1 in rosuvastatin pharmacokinetics

The Association between ABCG2 421C>A (rs2231142) Polymorphism and Rosuvastatin Pharmacokinetics: A Systematic Review and Meta-Analysis

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