Application of microdialysis to characterize drug disposition in pharmacokinetic studies: The case of methotrexate
Despite many chemotherapeutic successes in recent years against hematological cancers, anticancer drugs have had a more limited impact on solid tumors. Preliminary clinical investigations in breast cancer patients have suggested that concentrations of anticancer agents in the tumor may correlate with the response to chemotherapy. Studies have also demonstrated that many drugs do not distribute homogeneously in the body but rather yield varying concentrations in different tissues, and that tissue concentrations are more predictive of clinical outcome than plasma concentrations. The therapeutic response of tumors to methotrexate (MTX) can be hindered by suboptimal tissue/target site concentrations and the development of drug resistance due to active drug efflux. Previous attempts to utilize MTX plasma levels as an indicator of tumor response to therapy have generally failed. In this study, considerations of using the microdialysis methodology were examined to investigate the feasibility of obtaining pharmacokinetic (PK) data at the tumor site using tumor bearing animals and to understand MTX biodistribution in peripheral tissues both in small and large animal models. This study aimed to investigate the biodistribution of MTX, and its active metabolite, 7-OH-MTX, in the rat, mouse, and monkey models. Also, the impact of prior administration of known transporter inhibitors, probenecid and cyclosporine, alone and in combination, on plasma and tumor pharmacokinetic profiles of MTX was investigated. This study revealed significant differences in the relative estimated PK parameters of the plasma, subcutaneous (SC), peri- and intratumoral zones, all of which indicated that microdialysis is a valuable tool to study drug biodistribution in animal models. Additionally, co-administration of MTX with cyclosporine enhanced the intratumoral exposure levels whereas co-administration of MTX with probenecid alone, or probenecid and cyclosporine in combination caused a longer intratumoral half-life. This type of information may ultimately enable a better understanding of exposure-response relationships that can aid in the development of improved anticancer drug products and therapeutic outcomes.