Chu B C, Howell S B
J Pharmacol Exp Ther. 1981 Nov;219(2):389-93.
The pharmacokinetics and therapeutic effectiveness of methotrexate (MTX) and MTX covalently bound to bovine serum albumin (MTX-BSA) and poly-l-lysine, MW 3,000 (MTX-PLL 3K) or MW 40,000 to 60,000 (MTX-PLL 40-60K) were compared when these drugs were injected directly into the pleural cavities of BDF1 mice containing the L1210 tumor. Simultaneous measurements od drug levels in both pleural fluid and blood after a single dose demonstrated that free MTX and MTX-PLL 3K were cleared from the pleural cavity and blood within 4 hr, MTX-PLL 40K-60K was cleared within 2 hr, and MTX-BSA was still present in the tumor compartment at 48 hr. The coupling of MTX to these carriers increased its toxicity by extending the half-life of MTX-BSA within the animal and by incorporating a toxic PLL derivative as a carrier. At equitoxic doses, a single dose of MTX-BSA gave a peak increase in lifespan (ILS) of 50% (at 35 mg/kg) compared with a peak ILS of 30 to 35% for both free drug (at 95 mg/kg) and the MTX-PLL derivatives (at 1.4-6 mg/kg). Systemic administration of sufficient leucovorin to provide partial marrow protection compromised the antitumor activity of both MTX and MTX-BSA in the pleural cavity, and although leucovorin permitted higher doses to be used, this resulted in only a small increase in peak ILS for MTX-BSA on a single dose schedule.
将甲氨蝶呤（MTX）、与牛血清白蛋白共价结合的甲氨蝶呤（MTX - BSA）以及与分子量为3000的聚 - L - 赖氨酸（MTX - PLL 3K）或分子量为40000至60000的聚 - L - 赖氨酸（MTX - PLL 40 - 60K）直接注射到患有L1210肿瘤的BDF1小鼠的胸腔内后，比较了它们的药代动力学和治疗效果。单次给药后同时测量胸腔积液和血液中的药物水平表明，游离MTX和MTX - PLL 3K在4小时内从胸腔和血液中清除，MTX - PLL 40K - 60K在2小时内清除，而MTX - BSA在48小时时仍存在于肿瘤区室中。MTX与这些载体的偶联通过延长MTX - BSA在动物体内的半衰期以及将有毒的PLL衍生物作为载体而增加了其毒性。在等效毒性剂量下，单剂量的MTX - BSA使寿命峰值增加（ILS）50%（35mg/kg时），而游离药物（95mg/kg时）和MTX - PLL衍生物（1.4 - 6mg/kg时）的ILS峰值为30%至35%。全身给予足够的亚叶酸以提供部分骨髓保护会损害MTX和MTX - BSA在胸腔内的抗肿瘤活性，并且尽管亚叶酸允许使用更高的剂量，但这仅导致单剂量方案下MTX - BSA的ILS峰值略有增加。
