Alexander J, Fromtling R A, Bland J A, Pelak B A, Gilfillan E C
INTERx Research Corporation, Merck Sharp and Dohme Research Laboratories, Lawrence, Kansas 66047.
J Med Chem. 1991 Jan;34(1):78-81. doi: 10.1021/jm00105a013.
As a new prodrug approach to norfloxacin (NFLX) we prepared the acetoxyalkyl carbamates of the type NFLX-CO-OCHR-OAc by the reaction of sodium or mercuric acetate on NFLX alpha-chloroalkyl carbamates. These produrgs did not have the bitter taste of NFLX. In vitro, the acetoxyethyl carbamate exhibited activity only against Staphylococcus spp. and was inactive against Gram-negative organisms. However, in the presence of serum and intestinal homogenate, esterase-catalyzed hydrolysis of the ester bond in these modified carbamates led to a cascade reaction resulting in the rapid regeneration of NFLX. At high oral doses of the prodrug, the acetaldehyde produced as a side product in the breakdown of the promoiety caused a slight decrease in alcohol metabolism in a mouse model. The bioavailability of NFLX from the acetoxyethyl carbamate was lower compared to an equivalent dose of NFLX when given as an oral suspension in rhesus monkeys, presumably because of the lower aqueous solubility of the prodrug.
作为诺氟沙星（NFLX）的一种新的前药方法，我们通过乙酸钠或乙酸汞与NFLXα-氯烷基氨基甲酸酯反应，制备了NFLX-CO-OCHR-OAc类型的乙酰氧基烷基氨基甲酸酯。这些前药没有NFLX的苦味。在体外，乙酰氧基乙基氨基甲酸酯仅对葡萄球菌属有活性，对革兰氏阴性菌无活性。然而，在血清和肠匀浆存在的情况下，这些修饰的氨基甲酸酯中酯键的酯酶催化水解导致级联反应，从而使NFLX迅速再生。在前药高口服剂量时，前体部分分解过程中作为副产物产生的乙醛在小鼠模型中导致酒精代谢略有下降。当在恒河猴中以口服混悬液形式给药时，与等量的NFLX相比，乙酰氧基乙基氨基甲酸酯中NFLX的生物利用度较低，这可能是因为前药的水溶性较低。
