Takata J, Karube Y, Hanada M, Matsunaga K, Iwasaki H
Faculty of Pharmaceutical Sciences, Fukuoka University, Japan.
Biol Pharm Bull. 1999 Feb;22(2):172-8. doi: 10.1248/bpb.22.172.
The N,N-dimethylglycine esters of menahydroquinone-4 (1-mono, 1; 4-mono, 2; 1,4-bis, 3) were established in previous reports as prodrugs that could achieve the systemic bioreductive activation-independent delivery of menahydroquinone-4 (MKH), the active form of menaquinone-4 (MK-4), in rat. The present study was undertaken to investigate if the prodrugs could undergo cleavage to parent drug (MKH) by a human tissues enzyme catalyzed hydrolytic pathway, the mechanism of the prodrugs for vitamin K-dependent carboxylation in human liver and their action in the warfarin poisoned human liver. The hydrolysis of the esters was shown to be catalyzed by esterases located in human liver but not in human plasma. The susceptibility of the esters to undergo human liver esterase hydrolysis was affected by the esterified position: 1>2>3. By using a human liver microsomal test system, the stimulation of vitamin K-dependent carboxylation with the prodrugs was determined. The prodrug could stimulate the carboxylation activity in the absence of dithiothreitol, an artificial activator of the reductive activation pathway of MK-4. The carboxylation activity of the prodrug was strongly inhibited in the presence of eserine, an esterase inhibitor. The prodrug could also stimulate the carboxylase under warfarin-poisoned conditions, where the vitamin K cycle was strongly inhibited. The results confirmed that the prodrug could generate MKH in human liver (active site), and that the resultant MKH could act as a cofactor for the carboxylase without reductive activation processes of MK-4 to MKH. Such bioreductive activation-independent vitamin K-dependent carboxylation characteristic of the prodrug leads to enhanced pharmacological efficacy in the treatment of hypoprothrombinaemia induced in patients with coumarin and cephalosporin therapies.
在之前的报道中已证实，甲萘醌-4（1-单酯，1；4-单酯，2；1,4-双酯，3）的N,N-二甲基甘氨酸酯作为前药，可在大鼠体内实现甲萘醌-4（MK-4）的活性形式——甲萘氢醌-4（MKH）的全身生物还原激活非依赖性递送。本研究旨在调查这些前药是否能通过人体组织酶催化的水解途径裂解为母体药物（MKH），研究这些前药在人肝脏中维生素K依赖性羧化的机制及其在华法林中毒人肝脏中的作用。结果表明，这些酯的水解是由人肝脏中的酯酶催化的，而不是人血浆中的酯酶。酯的酯化位置会影响其对人肝脏酯酶水解的敏感性：1>2>3。通过使用人肝脏微粒体测试系统，测定了前药对维生素K依赖性羧化的刺激作用。在前药存在的情况下，在不存在二硫苏糖醇（MK-4还原激活途径的人工激活剂）的情况下，前药可刺激羧化活性。在存在酯酶抑制剂毒扁豆碱的情况下，前药的羧化活性受到强烈抑制。在前药存在的情况下，在华法林中毒条件下（此时维生素K循环受到强烈抑制），前药也能刺激羧化酶。结果证实，前药可在人肝脏（活性部位）中生成MKH，生成的MKH可作为羧化酶的辅因子，而无需MK-4到MKH的还原激活过程。这种前药的生物还原激活非依赖性维生素K依赖性羧化特性导致在治疗香豆素和头孢菌素治疗患者中诱导的低凝血酶原血症时药理疗效增强。
