PHARMACOKINETICS OF METHOTREXATE AFTER INTRAVENOUS-INFUSION OF METHOTREXATE-RABBIT SERUM-ALBUMIN CONJUGATE TO RABBITS

The pharmacokinetics of methotrexate (MTX) were compared after 30 min intravenous infusion of the same dose (10 mg/kg as MTX) of MTX (treatment I) or MTX-rabbit serum albumin (RSA) conjugate (treatment II) to rabbits. In treatment II, the mean peak plasma level of MTX was significantly lower (48.1 vs 13.8-mu-g/ml), and plasma levels declined more slowly thereafter (mean apparent half-lives of 3.26 vs 4.96 h) than those in treatment I. In treatment II, the values of AUC (2360 vs 1510-mu-g min ml-1) and CL(R) (2.49 vs 0.452 ml min-1 kg-1) were decreased, however, the values of V(SS) (0.311 vs 1.47 1/kg), MRT (1.62 vs 3.71 h), t1/2 (3.26 vs 4.96 h), and CL(NR) (1.66 vs 6.13 ml min-1 kg-1) were significantly increased. The above data suggested that MTX resides longer in the rabbit, and that nonrenal metabolism of MTX increases in treatment II. It could be explained by the fact that MTX is released slowly from MTX-RSA conjugate, and that the disposition of MTX is saturable. The amounts of MTX (mu-g/g tissue) remaining in kidney, stomach, small intestine, and large intestine after 30 min infusion of MTX-RSA conjugate were 33, 6.1, 3.1, and 10 times lower, respectively, than those after 30 min infusion of free MTX. It might suggest that the administration of MTX-SA conjugate has less side effects of MTX in these organs or tissues than those of free MTX. The in vitro release of MTX from MTX-RSA conjugate in phosphate buffer of pH 7.4, the buffer with protease, rat liver homogenate, or human plasma was biphasic process. For example, an initial rapid release over approx. 6 h appears to be due to physically adsorbed MTX with the slower secondary release due to covalently bound drug. The release of MTX from the conjugate in vitro was accelerated in the presence of protease or liver homogenate.