Pharmacokinetics and Biodistribution of Pegylated Methotrexate after IV Administration to Mice

The efficacy of methotrexate (mtx) as an antimetabolite chemotherapeutic agent highly depends on its blood circulation half-life. in our previous study, different conjugates of mtx (mtx-peg) were synthesized, their physicochemical properties were investigated and mtx-peg5000 was finally selected as optimum drug-conjugate for further investigations. in the current work, first the stability of mtx-peg5000 was studied at 37 °c and the results indicated its high stability in plasma (t_1/2 = 144 h) and a relatively rapid degradation in tissuehomogenate (t_1/2 = 24 h). the study of protein binding pointed out that the conjugate washighly protein-bound (95%). the results of pharmacokinetic studies in mice indicated that mtx-peg5000 had longer plasma distribution and elimination half-lives compared to free mtx (t_1/2α 9.16 min for mtx-peg5000 versus 2.45 min for mtx and t_1/2 ß 88.44 for mtx- peg5000 versus 24.33 min for mtx). pharmacokinetic parameters also showed higher areaunder the curve (auc) of conjugate compared to parent drug (12.33 mg.ml^-1.min for mtx- peg5000 versus 2.64 mg.ml^-1.min for mtx). the biodistribution studies demonstrated that mtx-peg5000 did not highly accumulate in liver and intestine and had a mild and balanced distribution to other organs. also, the conjugate was measurable in tissues up to 48 h after injection and was detected in the brain, suggesting the possibility of delivering drug to braintumors.