Pharmacokinetics and organ-distribution of ³h-methotrexate and ³h-methotrexate-human serum albumin conjugates in mice

This investigation has been made to elucidate the pharmacokinetics and organ distribution of ³H-methotrexate (MTX) and ³H-MTX-human serum albumin (HSA) conjugate in mice and evaluate the feasibility to develop MTX-HSA conjugate as a useful anticancer delivery system. ³H-MTX-HSA conjugate was synthesized by coupling of ³H-MTX with HSA by carbodiimide reaction using EDC. ³H-MTX (treatment I) and ³H-MTX-HSA conjugates (treatment II) were injected intravenously via tail vein of ICR mice. At the designated time, blood was collected via heart puncture, and 4 mice were sacrificed. The liver, spleen, kidney, and lung were excised, and total radioactivity was measured. The mean plasma total radioactivity declined polyexponentially with a mean terminal half-life of 2.7 days from treatment I, however, the radioactivity declined rapidly for up to 3 days after the dose and decreased very slowly thereafter for up to 21 days after the dose. The mean AUQ in the liver, kidney, spleen, and lung was higher from treatment II than that from treatment 1. It clearly indicated that ³H-MTX-HSA conjugates were more uptaken into the organ than that of ³H-MTX, and ³H-MTX was released slowly from the conjugates. In treatment II, the weighted-average overall drug targeting efficiency(Te) for the liver was higher than in treatment 1 (86.4 vs 67.8% and the weighted-average relative tissue exposure(Re) was 6.4 for the liver. It suggested that administration of ³H-MTX-HSA conjugates might have good targeting ability to the liver.