Kawaguchi T, Ishikawa K, Seki T, Juni K
Faculty of Pharmaceutical Sciences, Josai University, Saitama, Japan.
J Pharm Sci. 1990 Jun;79(6):531-3. doi: 10.1002/jps.2600790616.
Ten novel ester prodrugs of zidovudine (azidothymidine; AZT) were synthesized with aliphatic acids (acetic-stearic), and the enzymatic regeneration of AZT from the prodrugs was investigated both in vitro and in vivo. The enzymatic hydrolysis rates of the AZT esters in the presence of mouse enzyme systems (plasma, liver, and intestine, and kidney) were highly dependent on the lengths of the acyl chains of the prodrugs. The caprate or caprylate of AZT showed the highest reactivity to three of the four enzyme systems; either the decrease or the increase in the acyl chain length resulted in the decrease of the reactivity to the enzymes. Zidovudine (AZT) and three of the prodrugs (acetate, caprate, and stearate) were administered to mice intraperitoneally, and the plasma concentrations of AZT and a corresponding prodrug were measured. The AZT concentrations in plasma following the acetate administration rapidly decreased with a half-life of 14.5 min. This tendency is similar to that shown in direct AZT administration. On the other hand, the concentrations following the caprate or stearate administration decreased slowly and were maintained for as long as 4 h after dosing. The prodrug concentrations in plasma after the prodrug administration were under the detection limit (0.01 micrograms/mL), except for acetate. The absence of the caprate and stearate in plasma may be attributed to the high hydrophobicity or favorable tissue distribution of the ester derivatives.
用脂肪酸（乙酸 - 硬脂酸）合成了10种新型齐多夫定（叠氮胸苷；AZT）酯前药，并在体外和体内研究了前药中AZT的酶促再生。在小鼠酶系统（血浆、肝脏、肠道和肾脏）存在下，AZT酯的酶促水解速率高度依赖于前药酰基链的长度。AZT的癸酸酯或辛酸酯对四种酶系统中的三种表现出最高的反应活性；酰基链长度的减少或增加都会导致对酶的反应活性降低。将齐多夫定（AZT）和三种前药（乙酸酯、癸酸酯和硬脂酸酯）腹腔注射给小鼠，并测量血浆中AZT和相应前药的浓度。乙酸酯给药后血浆中的AZT浓度迅速下降，半衰期为14.5分钟。这种趋势与直接给予AZT时相似。另一方面，癸酸酯或硬脂酸酯给药后的浓度下降缓慢，给药后长达4小时保持稳定。除乙酸酯外，前药给药后血浆中的前药浓度低于检测限（0.01微克/毫升）。血浆中不存在癸酸酯和硬脂酸酯可能归因于酯衍生物的高疏水性或良好的组织分布。
