Document Type: Research article
Department of Pharmaceutics, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
Center for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences, Shiraz, Iran.
Depratment of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Department of Pharmaceutics, School of Pharmacy & Protein Technology Research Center, Shahid Beheshti University of Medical Sciences,Tehran, Iran.
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 (T1/2 = 144 h) and a relatively rapid degradation in tissue homogenate (T1/2 = 24 h). The study of protein binding pointed out that the conjugate is highly 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 (T1/2 α 9.16 min for MTX-PEG5000 versus 2.45 min for MTX and T1/2 β 88.44 for MTX-PEG5000 versus 24.33 min for MTX). Pharmacokinetic parameters also showed higher area under 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 brain tumors.