Takata J, Karube Y, Hanada M, Matsunaga K, Matsushima Y, Sendo T, Aoyama T
Faculty of Pharmaceutical Sciences, Fukuoka University, Japan.
Pharm Res. 1995 Jan;12(1):18-23. doi: 10.1023/a:1016274201137.
The efficacy and toxicity of vitamin K depends on the pathway and the extent of enzymatic reductive activation to vitamin K hydroquinone, which is an essential cofactor for the synthesis of clotting factors. Parenteral use of vitamin K is impaired by its water insolubility. With the aim to improve delivery problems associated with menahydroquinone-4 (MKH, 2), an active form of menaquinone-4, N,N-dimethylglycine esters of 2 (1-mono, 4-mono, and 1,4-bis) were synthesized and assessed as potential water-soluble prodrugs for parenteral use. The esters can deliver the hydroquinone to its active site without a quinone reductive activation step. The hydrochloride salts of the esters were found to be quite soluble in water. The hydrolysis of the esters in 20% rat liver homogenate 9000 x g supernatant, rat plasma and phosphate buffer, pH 7.4, at 37 degrees C was kinetically studied in the presence and absence of an esterase inhibitor. The hydrolysis was catalyzed by esterases located in the rat liver and rat plasma and quantitatively yielded 2. These results suggest that esterification of 2 with N,N-dimethylglycine is a promising way for obtaining water-soluble prodrug forms of 2. Based on the high susceptibility to liver esterase, the esters are potential prodrugs for achieving the site-specific delivery of 2.
维生素K的功效和毒性取决于其向维生素K氢醌酶促还原活化的途径和程度，维生素K氢醌是凝血因子合成所必需的辅助因子。维生素K的水溶性不佳，影响了其肠胃外给药的效果。为了解决与甲萘氢醌-4（MKH，2）相关的给药问题，甲萘醌-4的一种活性形式，合成了2（1-单酯、4-单酯和1,4-双酯）的N,N-二甲基甘氨酸酯，并评估其作为肠胃外给药潜在水溶性前药的可能性。这些酯无需醌还原活化步骤就能将氢醌输送到其活性位点。发现这些酯的盐酸盐在水中溶解度相当高。在有和没有酯酶抑制剂的情况下，对酯在20%大鼠肝脏匀浆9000×g上清液、大鼠血浆和pH 7.4的磷酸盐缓冲液中于37℃水解进行了动力学研究。水解由大鼠肝脏和大鼠血浆中的酯酶催化，并定量生成2。这些结果表明，用N,N-二甲基甘氨酸对2进行酯化是获得2水溶性前药形式的一种有前景的方法。基于对肝脏酯酶的高敏感性，这些酯是实现2位点特异性递送的潜在前药。
