Shao Z, Park G B, Krishnamoorthy R, Mitra A K
Department of Industrial and Physical Pharmacy, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907-1336.
Pharm Res. 1994 Feb;11(2):237-42. doi: 10.1023/a:1018903407592.
A series of 2'-(O-acyl) derivatives of 9-(2-hydroxyethoxymethyl)guanine (acyclovir) was synthesized by acid anhydride esterification. Aqueous solubilities in isotonic phosphate buffer (pH 7.4), partition coefficients in 1-octanol/phosphate buffer, and hydrolysis kinetics in rat plasma were determined. The ester prodrugs showed consistent increases in lipophilicity with corresponding decreases in aqueous solubility as a function of side-chain length. The bioconversion kinetics of the prodrugs appear to depend on both the apolar and the steric nature of the acyl substituents. When perfused through the rat nasal cavity using the in situ perfusion technique, acyclovir showed no measurable loss from the perfusate. Nasal uptake of acyclovir prodrugs, on the other hand, were moderately improved. Furthermore, the extent of nasal absorption appears to depend on the lipophilicity of the prodrugs in the descending order hexanoate > valerate > pivalate > butyrate. Simultaneous prodrug cleavage by nasal carboxylesterase was also noted in the case of hexanoate.
通过酸酐酯化反应合成了一系列9-(2-羟基乙氧基甲基)鸟嘌呤（阿昔洛韦）的2'-(O-酰基)衍生物。测定了其在等渗磷酸盐缓冲液（pH 7.4）中的水溶性、在1-辛醇/磷酸盐缓冲液中的分配系数以及在大鼠血浆中的水解动力学。酯前药的亲脂性随着侧链长度的增加而持续增加，水溶性相应降低。前药的生物转化动力学似乎取决于酰基取代基的非极性和空间性质。使用原位灌注技术经大鼠鼻腔灌注时，阿昔洛韦在灌注液中没有可测量的损失。另一方面，阿昔洛韦前药的鼻腔摄取有适度改善。此外，鼻腔吸收程度似乎取决于前药的亲脂性，顺序为己酸酯>戊酸酯>新戊酸酯>丁酸酯。在己酸酯的情况下，还观察到鼻腔羧酸酯酶同时进行前药裂解。
