The effects of drug transporter inhibitors on the pharmacokinetics and tissue distribution of methotrexate in normal and tumor-bearing mice: a microdialysis study

Abstract

To examine methotrexate (MTX) tumor delivery in a mouse model using an in vivo microdialysis technique and to characterize the impact of prior administration of the known transporter inhibitors probenecid and cyclosporine (CsA), alone and in combination, on plasma and tumor pharmacokinetics of MTX. Different groups of mice were used to evaluate the plasma pharmacokinetics of MTX and the impact of prior administration of probenecid and/or CsA on the plasma pharmacokinetics. Xenografted nude mice were used for microdialysis experiments to measure the subcutaneous (SC), peri- and intratumoral pharmacokinetics of MTX without and with coadministration of probenecid, CsA, and both probenecid and CsA. The SC dialysates in pre-treated groups demonstrated a delayed disappearance and an enhanced MTX exposure. Similar effects were observed in the tumor peripheral zone. However, this increase was less pronounced. The central tumor findings demonstrated that CsA had a more significant impact on the enhancement of MTX exposure. Probenecid did not increase the exposure of MTX inside the tumor, but caused a longer half-life of central MTX. This study revealed significant differences in the relative estimated PK parameters of the plasma, SC, peri-, and intratumoral zones. Additionally, this study demonstrated that the coadministration of MTX with CsA can enhance the intratumoral exposure levels of the drug, whereas coadministration of MTX with probenecid alone, or with a combination of probenecid and CsA, increases intratumoral half-life.