Silencing drug transporters in human primary muscle cells modulates atorvastatin pharmacokinetics: A pilot study

Background and Purpose

Non-adherence to atorvastatin treatment is relatively common and partly due to statin-related myotoxicities (SRMs). The risk of developing SRM is dose- and concentration-dependent, highlighting the importance of atorvastatin pharmacokinetics. This study explored the inter-individual variabilities in expression of the atorvastatin transporter gene contributing to modulation of atorvastatin within the muscle cell.

Experimental Approach

mRNA levels of efflux and influx transporters were measured and modulated with siRNAs to evaluate effects on intracellular accumulation of atorvastatin in primary cultures of differentiated myotubes from 12 human volunteers.

Key Results

All genes assessed were expressed with a high inter-individual variability. In differentiated myotubes, efflux transporters were expressed at higher levels than the influx carriers. When considering efflux and influx transporters separately, ABCC1 and SLCO2B1 are the most highly expressed efflux and influx transporters. Suppression of ABCC1, ABCC4 and/or ABCG2 mRNA levels with siRNA significantly increased intracellular accumulation of atorvastatin in differentiated myotubes. Interestingly, the siRNA targeting ABCG2 had a moderate effect on intracellular accumulation of atorvastatin in a volunteer expressing the ABCG2 variant rs2231142 (c.421C>A, p.Gln141Lys). This hypothesis was further validated in a HEK recombinant model overexpressing ABCG2 either wild-type (421C) or variant (421A). Reduction of SLCO1B1 and SLCO2B1 mRNA levels significantly modified intracellular accumulation of atorvastatin in only some volunteers, depending on the expression levels of transporters.

Conclusion and Implications

Silencing ABCC1, ABCC4 or ABCG2 expression alters accumulation of atorvastatin in myotubes, whereas the effect of silencing influx transporters depends on the expression of these transporters.