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We read with interest the paper by Ranganathan et al proposing that pharmacogenetics may be a useful tool to help predict methotrexate (MTX) toxicity and efficacy in rheumatoid arthritis (RA).1
One aspect they highlight is the potential role of drug efflux mechanisms in contributing to the lack of response to MTX in some patients. It is important to note that although they discuss the drug efflux transporter P-glycoprotein (P-gp) as being of interest, the paper they cite in support of this view actually reports an experiment in which MTX resistance was mediated by a different drug transporter, multidrug resistance protein 1 (MRP1).2 A range of efflux transporters have been described, including P-gp, MRP, and breast cancer resistance protein (BCRP). Different drugs appear to be substrates for different efflux transporters.3 The drug transporter that mediates MTX resistance remains somewhat controversial.
Llorente et al studied 16 patients with RA and found higher P-glycoprotein (P-gp) levels in patients who were defined as being refractory to disease modifying drug treatment than in treatment responders.4 Similarly, Norris et al demonstrated increased P-gp expression in leukaemic cell lines resistant …