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

Abstract

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.

Prediction of Drug Distribution in Subcutaneous Xenografts of Human Tumor Cell Lines and Healthy Tissues in Mouse: Application of the Tissue Composition-Based Model to Antineoplastic Drugs

“…The chemical structures of these compounds are diverse, and the group includes charged bases and acids as well as uncharged (neutral) molecules at physiological pH as characterized by the ionization constant (p K a). For these drugs, the observed unbound fraction in plasma (fu p ) ranged from 0.012 to 0.99, the lipophilicity (log n ‐octanol–water partition coefficient; log P ) ranged from −0.89 to 4.26, and the volume of distribution at steady state in mouse ranged from 0.25 to more than 50 L/kg; therefore, the current dataset covers a large range of physicochemical and tissue distribution properties (Table ).…”

“…Calculated as the ratio between hepatic blood CL and the liver blood flow rate assumed in a standard mouse (120 mL/min kg) …”

Microdialysis-directed Intra-tumor Pharmacokinetic Modeling of Methotrexate in Mice and Humans

“…This deficiency provided us with the impetus to develop a more comprehensive pre-clinical PK model of MTX in breast tumors that could subsequently be scaled to predict human breast MTX concentrations. In this study, MTX concentration-time profiles that we previously obtained from plasma and tumor (22,23) were used to develop a hPBPK model to better describe MTX disposition in solid tumor and to more precisely predict MTX concentrations in the tumor.…”

“…Details of experimental procedures have been described in our previous investigation (22,23). Briefly, 200 mg/kg MTX was intravenously injected into two groups of mice (CD-1 or nude strain).…”

“…Microdialysis probes (2 µL/min flow rate) were used to collect the unbound drug after the equilibrium from the core of the tumor at time periods of 10 min to 120 min with an interval of every 10 min (n=3). The HPLC method was used to quantify MTX concentrations from collected samples using the method described in our previous publication (23). All the raw data, instead of the mean values, were used in the pharmacokinetic analysis based on the pharmacokinetic model introduced below.…”