Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Dec 30;26(1):260.
doi: 10.3390/ijms26010260.

Effect of Genetic Variants on Rosuvastatin Pharmacokinetics in Healthy Volunteers: Involvement of ABCG2, SLCO1B1 and NAT2

Eva González-Iglesias  1   2 , Clara Méndez-Ponce  1 , Dolores Ochoa  1   2 , Manuel Román  1 , Gina Mejía-Abril  1 , Samuel Martín-Vilchez  1 , Alejandro de Miguel  1 , Antía Gómez-Fernández  1   2 , Andrea Rodríguez-Lopez  1   2 , Paula Soria-Chacartegui  1   2 , Francisco Abad-Santos  1   2   3 , Jesús Novalbos  1
Affiliations

Effect of Genetic Variants on Rosuvastatin Pharmacokinetics in Healthy Volunteers: Involvement of ABCG2, SLCO1B1 and NAT2

Eva González-Iglesias et al. Int J Mol Sci. .

Abstract

Statins are the primary drugs used to prevent cardiovascular disease by inhibiting the HMG-CoA reductase, an enzyme crucial for the synthesis of LDL cholesterol in the liver. A significant number of patients experience adverse drug reactions (ADRs), particularly musculoskeletal problems, which can affect adherence to treatment. Recent clinical guidelines, such as those from the Clinical Pharmacogenetics Implementation Consortium (CPIC) in 2022, recommend adjusting rosuvastatin doses based on genetic variations in the ABCG2 and SLCO1B1 genes to minimize ADRs and improve treatment efficacy. Despite these adjustments, some patients still experience ADRs. So, we performed a candidate gene study to better understand the pharmacogenetics of rosuvastatin. This study included 119 healthy volunteers who participated in three bioequivalence trials of rosuvastatin alone or in combination with ezetimibe at the Clinical Trials Unit of the Hospital Universitario de La Princesa (UECHUP). Participants were genotyped using a custom OpenArray from ThermoFisher that assessed 124 variants in 38 genes associated with drug metabolism and transport. No significant differences were observed according to sex or biogeographic origin. A significant increase in t1/2 (pmultivariate(pmv) = 0.013) was observed in the rosuvastatin plus ezetimibe trial compared with the rosuvastatin alone trials. Genetic analysis showed that decreased (DF) and poor function (PF) volunteers for the ABCG2 transporter had higher AUC∞/DW (adjusted dose/weight), AUC72h/DW and Cmax/DW compared to normal function (NF) volunteers (pmv< 0.001). DF and PF volunteers for SLCO1B1 showed an increase in AUC72h/DW (pmv = 0.020) compared to increased (IF) and NF individuals. Results for ABCG2 and SLCO1B1 were consistent with the existing literature. In addition, AUC∞/DW, AUC72h/DW and Cmax/DW were increased in intermediate (IA) and poor (PA) NAT2 acetylators (pmv = 0.001, pmv< 0.001, pmv< 0.001, respectively) compared to rapid acetylators (RA), which could be associated through a secondary pathway that was previously unknown.

Keywords: clinical trials; musculoskeletal side effects; pharmacogenetics; pharmacokinetics; rosuvastatin; statins.

PubMed Disclaimer

Conflict of interest statement

Francisco Abad-Santos and Dolores Ochoa have been consultants or investigators in clinical trials sponsored by the following pharmaceutical companies: Abbott, Alter, Aptatargets, Chemo, Cinfa, FAES, Farmalíder, Ferrer, GlaxoSmithKline, Galenicum, Gilead, Italfarmaco, Janssen-Cilag, Kern, Moderna, MSD, Normon, Novartis, Servier, Silver Pharma, Teva and Zambon. The remaining authors declare no conflicts of interest.

References

    1. Catapano A.L., Graham I., De Backer G., Wiklund O., Chapman M.J., Drexel H., Hoes A.W., Jennings C.S., Landmesser U., Pedersen T.R., et al. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. Eur. Heart J. 2016;37:2999–3058. doi: 10.1093/eurheartj/ehw272. - DOI - PubMed
    1. Nabel E.G. Cardiovascular disease. N. Engl. J. Med. 2003;349:60–72. doi: 10.1056/NEJMra035098. - DOI - PubMed
    1. Khanji M.Y., van Waardhuizen C.N., Bicalho V.V.S., Ferket B.S., Hunink M.G.M., Petersen S.E. Lifestyle advice and interventions for cardiovascular risk reduction: A systematic review of guidelines. Int. J. Cardiol. 2018;263:142–151. doi: 10.1016/j.ijcard.2018.02.094. - DOI - PubMed
    1. Roth G.A., Mensah G.A., Johnson C.O., Addolorato G., Ammirati E., Baddour L.M., Barengo N.C., Beaton A.Z., Benjamin E.J., Benziger C.P., et al. Global Burden of Cardiovascular Diseases and Risk Factors, 1990–2019: Update From the GBD 2019 Study. J. Am. Coll. Cardiol. 2020;76:2982–3021. doi: 10.1016/j.jacc.2020.11.010. - DOI - PMC - PubMed
    1. Liao J.K. Effects of Statins on 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibition Beyond Low-Density Lipoprotein Cholesterol. Am. J. Cardiol. 2005;96:24F–33F. doi: 10.1016/j.amjcard.2005.06.009. - DOI - PMC - PubMed

MeSH terms

Substances

LinkOut - more resources