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

Taskinen Suvi; Viinamäki Jenni; Tarkiainen E Katriina; Tapaninen Tuija; Tornio Aleksi; Paile-Hyvarinen Maria; Backman Janne T; Neuvonen Mikko; Niemi Mikko; Lilius Tuomas O; Lehtisalo Minna
A comprehensive pharmacogenomic study indicates roles for SLCO1B1, ABCG2 and SLCO2B1 in rosuvastatin pharmacokinetics

Taskinen Suvi
Viinamäki Jenni
Tarkiainen E Katriina
Tapaninen Tuija
Tornio Aleksi
Paile-Hyvarinen Maria
Backman Janne T
Neuvonen Mikko
Niemi Mikko
Lilius Tuomas O
Lehtisalo Minna
Katso/Avaa
Lataukset: 

WILEY
doi:10.1111/bcp.15485
URI
https://doi.org/10.1111/bcp.15485
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Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe2022091258507
Tiivistelmä

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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