Statins are one of the most widely prescribed medications globally, primarily used to lower LDL cholesterol and reduce the risk of cardiovascular events such as heart attacks and strokes. While their effectiveness in preventing heart disease is well-established, concerns about side effects persist, particularly as their use expands among aging populations and those with multiple risk factors. One of the more significant side effects is statin-associated myopathy, a condition characterized by muscle pain, weakness, and, in rare cases, serious muscle damage known as rhabdomyolysis. Although most cases are mild, myopathy can impact quality of life and lead to discontinuation of therapy.
Drug transporters are crucial in regulating the disposition of statins throughout the body, making the potential for drug-drug interactions (DDI) a significant concern - particularly in patients with multiple health conditions who often require polypharmacy. A recently published article by Tuomi et al. (2025) investigated the transport of the six statins simvastatin acid, atorvastatin, rosuvastatin, pitavastatin, pravastatin and fluvastatin by multidrug resistance-associated proteins (MRPs) 1 and 5 using inside-out membrane vesicles. Their study demonstrated that fluvastatin was a substrate of MRP1 and both fluvastatin, pitavastatin and atorvastatin were substrates of MRP5. Evaluating the data also strongly suggests that both rosuvastatin (uptake ratio 1.84) and simvastatin acid (uptake ratio 1.72) are substrates of MRP1 due to a clear separation in their uptake rates (pmol/min/mg) when accounting for standard deviation (minimum +ATP versus maximum +AMP conditions), despite not reaching mathematical significance. This work built on their earlier publication (Deng et al., 2021) which demonstrated that fluvastatin and rosuvastatin were also substrates of MRP4. The relevance of these findings is linked to the fact that MRP1, MRP4 and MRP5 are expressed on the cell membrane surface of human skeletal muscle fibres (Knauer et al., 2010) where they act to efflux drugs out of the myocytes and therefore play a protective role. As mentioned earlier, muscle toxicity is a serious side effect of statins. This toxic effect is dose- and concentration-dependent and can occur clinically when there is an increase in systemic statin exposure as a result of a pharmacokinetic DDI caused by a precipitant comedication. In turn,this can lead to elevated statin concentrations in myocytes. If the statin involved is a substrate of MRP1, MRP4 or MRP5, then these efflux transporters might help to reduce myocyte exposure thereby offering a degree of protection against muscle toxicity. However, if the interacting precipitant comedication is also capable of clinically inhibiting these MRP transporters then this could exacerbate the risk of myopathy.
Using our consultative approach and transporter science expertise at Cyprotex, we can evaluate your investigational drug as an inhibitor of the enzymes (CYP3A4 and CYP2C9) and transporters (BCRP, OATP1B1 and OAT3) that are critical to the clinical disposition of statins. Using the determined in vitro parameters obtained and our extensively published mechanistic static equation models (Elsby et al., 2018, 2022, 2023), Cyprotex can quantitatively predict the increase in exposure (AUCR) of simvastatin acid, atorvastatin, rosuvastatin, pitavastatin, pravastatin and fluvastatin that might be expected in a DDI with your drug. These predictions can help your clinical development team and physicians contextualize the pharmacokinetic DDI risk to understand if it could be clinically significant on a statin-by-statin basis. Furthermore, in light of the potential important roles MRP1/MRP4/MRP5 may play in modulating statin muscle exposure, identification of your drug as an inhibitor of MRPs could provide further insight towards overall risk.
Discuss your DDI study with our subject matter experts.
References
1) Deng F, et al., (2021) Comparative hepatic and intestinal efflux transport of statins. Drug Metab Dispos 49:750-759. https://doi.org/10.1124/dmd.12...
2) Elsby R, et al., (2019) Mechanistic in vitro studies indicate that the clinical drug-drug interaction between telithromycin and simvastatin acid is driven by time-dependent inhibition of CYP3A4 with minimal effect on OATP1B1. Drug Metab Dispos 47:1-8. https://doi.org/10.1124/dmd.11...
3) Elsby R, et al., (2022) Studying the right transporter at the right time: an in vitro strategy for assessing drug-drug interaction risk during drug discovery and development. Exp Opin Drug Metab Toxicol 18(10):619-655. https://doi.org/10.1080/174252...
4) Elsby R, et al., (2023) Mechanistic in vitro studies indicate that the clinical drug-drug interactions between protease inhibitors and rosuvastatin are driven by inhibition of intestinal BCRP and hepatic OATP1B1 with minimal contribution from OATP1B3, NTCP and OAT3. Pharmacol Res Perspect 11(2), 2023, e01060, https://doi.org/10.1002/prp2.1060.
5) Knauer MJ, et al., (2010) Human skeletal muscle drug transporters determine local exposure and toxicity of statins. Circ Res 106:297-306. https://doi.org/10.1161/circre...
6) Tuomi SK, et al., (2025) Transport of statins by multidrug resistance-associated proteins 1 and 5. Eur J Pharm Sci; 209:107070. https://doi.org/10.1016/j.ejps.2025.107070.
