用羧肽酶G2抢救实验性鞘内注射甲氨蝶呤过量

Rescue of experimental intrathecal methotrexate overdose with carboxypeptidase-G2.

作者信息

Adamson P C, Balis F M, McCully C L, Godwin K S, Bacher J D, Walsh T J, Poplack D G

机构信息

Pediatric Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.

出版信息

J Clin Oncol. 1991 Apr;9(4):670-4. doi: 10.1200/JCO.1991.9.4.670.

DOI:10.1200/JCO.1991.9.4.670

PMID:2066764

Abstract

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.

摘要

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。