Adamson P C, Balis F M, McCully C L, Godwin K S, Bacher J D, Walsh T J, Poplack D G
Pediatric Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
J Clin Oncol. 1991 Apr;9(4):670-4. doi: 10.1200/JCO.1991.9.4.670.
The carboxypeptidase G class of enzymes rapidly hydrolyze methotrexate (MTX) into the inactive metabolites 4-deoxy-4-amino-N10-methylpteroic acid (DAMPA) and glutamate. This study evaluated the use of carboxypeptidase-G2 (CPDG2) as a potential intrathecal (IT) rescue agent for massive IT MTX overdose. The CSF pharmacokinetics of MTX with and without CPDG2 rescue was studied in adult rhesus monkeys (Macaca mulatta) using a nontoxic IT 5 mg dose (equivalent to 50 mg in humans). Without CPDG2 rescue, peak CSF MTX concentration was 2,904 +/- 340 mumol/L. Within 5 minutes of administration of 30 U IT CPDG2, CSF MTX concentrations decreased greater than 400-fold to 6.55 +/- 6.7 microM. Subsequently, groups of three monkeys received either 25 mg IT MTX (equivalent to 250 mg in humans) followed by 150 U IT CPDG2 or 50 mg IT MTX (equivalent to 500 mg in humans) followed by 300 U IT CPDG2. All animals survived without neurotoxicity. Our studies suggest that CPDG2 may prove to be an important addition to the currently recommended strategy for the management of IT MTX overdose.
羧肽酶G类酶可迅速将甲氨蝶呤（MTX）水解为无活性的代谢产物4-脱氧-4-氨基-N10-甲基蝶酸（DAMPA）和谷氨酸。本研究评估了羧肽酶-G2（CPDG2）作为鞘内注射（IT）大剂量MTX过量潜在解救剂的用途。在成年恒河猴（猕猴）中，使用无毒的鞘内注射5 mg剂量（相当于人类50 mg）研究了有或无CPDG2解救时MTX的脑脊液药代动力学。在未进行CPDG2解救的情况下，脑脊液中MTX的峰值浓度为2,904±340 μmol/L。在鞘内注射30 U CPDG2后5分钟内，脑脊液中MTX浓度下降超过400倍，降至6.55±6.7 μM。随后，将三只猴子分为一组，分别接受25 mg鞘内注射MTX（相当于人类250 mg），随后注射150 U鞘内CPDG2，或50 mg鞘内注射MTX（相当于人类500 mg），随后注射300 U鞘内CPDG2。所有动物均存活且无神经毒性。我们的研究表明，CPDG2可能被证明是目前推荐的鞘内注射MTX过量管理策略的重要补充。
