Functional MRP1 activity in human skeletal muscle

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Statins, or 3-hydroxy-3-methylglutaryl-Coenzyme A (HMG-CoA) reductase inhibitors, are commonly prescribed medications that lower cholesterol, used to treat hypercholesterolemia and prevent cardiovascular events. Despite their clinical benefits, statin use is often discontinued due to statin-associated muscle symptoms. We have read with great interest the article by Hoste et al. (2025), in which the authors demonstrate that the adenosine triphosphate-binding cassette (ABC) transporter multidrug resistance-associated protein 1 (MRP1/ABCC1) is highly expressed in primary cultures of differentiated human skeletal muscle myotubes and regulates the intracellular concentration of atorvastatin. The authors also suggest that MRP1-mediated efflux transport may help protect skeletal muscle cells from statin-induced myopathy. This raises the possibility of MRP1-mediated drug–drug interactions (DDIs) in skeletal muscle cells, when patients receiving statin therapy are concurrently treated with MRP1-inhibiting drugs, such as the uricosuric agent probenecid (Dorajoo et al., 2008). These drug–drug interactions may occur without noticeable changes in plasma statin concentrations, potentially leading to increased intramuscular accumulation of statins and exacerbating statin-related muscle side effects. However, Hoste et al. (2025) observed some differences in transporter expression between primary cultures of differentiated myotubes and uncultured muscle biopsies, noting that their findings may not fully reflect the in vivo situation. To improve the clinical relevance of the findings by Hoste et al. (2025) and of other studies (Dorajoo et al., 2008; Knauer et al., 2010), obtaining in vivo evidence of functional MRP1 activity in human skeletal muscle would be highly desirable. Positron emission tomography (PET) imaging can be employed to assess the role of membrane transporters in the tissue distribution of radiolabelled drugs (Tournier et al., 2018). We recently conducted a first-in-human study using the PET tracer 6-bromo-7-[11C]methylpurine ([11C]BMP), which distributes to different tissues via passive diffusion and is rapidly and quantitatively converted intracellularly into the corresponding glutathione conjugate S-(6-(7-[11C]methylpurinyl))glutathione ([11C]MPG) (Figure 1a) (Jackwerth et al., 2025). The latter compound has a limited passive membrane permeability and is eliminated from tissues primarily via MRP1 and potentially by other MRP subtypes, such as MRP4/ABCC4. 6-bromo-7-[11C]methylpurine ([11C]BMP) PET scans were performed in healthy human subjects, both with and without pre-treatment with a single oral dose of probenecid (Jackwerth et al., 2025). In addition to inhibiting organic anion transporters 1 (OAT1/SLC22A6) and 3 (OAT3/SLC22A8), probenecid also inhibits various MRP subtypes, including MRP1. Our results showed reduced elimination of [11C]BMP-derived radioactivity from human skeletal muscle tissue following probenecid pre-treatment, which led to a significant increase in tissue exposure (Figure 1b). Building on the findings of Hoste et al. (2025), who identified MRP1 as the predominant MRP subtype in muscle biopsies, our results provide, to our knowledge, the first in vivo evidence of functional MRP1 activity in human skeletal muscle. Furthermore, our study supports the potential for MRP1-mediated drug–drug interactions in muscle tissue, involving MRP1-transported statin drugs (e.g. atorvastatin, simvastatin acid, rosuvastatin and pravastatin). Our data also underscore the utility of PET imaging for assessing drug concentrations in human tissues and for validating in vitro findings from cell culture experiments. M. Jackwerth: Conceptualization (equal); formal analysis (lead); visualization (lead); writing—review and editing (equal). S. Mairinger: Conceptualization (equal); writing—review and editing (equal). M. Zeitlinger: Conceptualization (equal); resources (lead); writing—review and editing (equal). O. Langer: Conceptualization (equal); funding acquisition (lead); project administration (lead); supervision (lead); writing—original draft (lead); writing—review and editing (equal). This research was funded by the Austrian Research Promotion Agency (FFG) (882717 PETABC, to Oliver Langer). PETABC is an EU Joint Programme - Neurodegenerative Disease Research (JPND) project. PETABC is supported through the following funding organisations under the aegis of JPND (www.jpnd.eu): NFR #327571 - Norway, FFG #882717 - Austria, BMBF #01ED2106 - Germany, MSMT #8F21002 - Czech Republic, VIAA #ES RTD/2020/26 - Latvia, ANR #20-JPW2–0002-04 - France and SRC #2020–02905 - Sweden. The authors declare no conflicts of interest.

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