Cook C S, Karabatsos P J, Schoenhard G L, Karim A
Department of Clinical Pharmacology, Searle Research and Development, Skokie, Illinois 60077, USA.
Pharm Res. 1995 Aug;12(8):1158-64. doi: 10.1023/a:1016259826037.
The in vitro fate of an ester prodrug, glycovir, was studied to determine if the species differences in the bioavailability of pharmacologically active SC-48334 observed after glycovir administration and not observed after SC-48334 administration is due to species differences in ester hydrolysis rate or species differences in absorption of the prodrug itself, and to determine the site(s) of ester hydrolysis which contributes most to species differences in the bioavailability of SC-48334 if any.
Glycovir was incubated with small intestinal mucosa, liver S9 fractions, whole blood, red blood cells (RBC) and plasma of the rat, dog, monkey (cynomolgus and rhesus) and man, and glycovir concentrations were determined by HPLC.
The relative bioavailabilities of SC-48334 after prodrug administration to the rat, dog, monkey and man were 99, 15, 42 and 37%, respectively. After SC-48334 administration, SC-48334 was rapidly and similarly well absorbed in all species. The hydrolysis rate in the small intestinal mucosa was well correlated with the relative bioavailability of SC-48334 after prodrug administration. Among different species the hydrolysis rate of glycovir in liver S9 fractions, blood, RBC and plasma did not parallel those in the mucosa of the small intestine.
The species differences in bioavailability of SC-48334 with the prodrug were due to species differences in hydrolysis rates of the prodrug in small intestinal mucosa. The monkey was a good animal model for prediction of esterase activity in human small intestine and relative bioavailability in man.
研究酯前药甘昔洛韦在体外的转归，以确定甘昔洛韦给药后观察到的、而SC-48334给药后未观察到的药理活性物质SC-48334生物利用度的种属差异，是由于酯水解速率的种属差异还是前药本身吸收的种属差异所致，并确定如果存在的话，对SC-48334生物利用度的种属差异贡献最大的酯水解部位。
将甘昔洛韦与大鼠、犬、猴（食蟹猴和恒河猴）及人的小肠黏膜、肝脏S9组分、全血、红细胞（RBC）和血浆一起孵育，并用高效液相色谱法测定甘昔洛韦浓度。
前药给药后，大鼠、犬及猴、人SC-48334的相对生物利用度分别为99%、15%、42%和37%。SC-48334给药后，SC-48334在所有种属中均迅速且吸收良好。小肠黏膜中的水解速率与前药给药后SC-48334的相对生物利用度密切相关。在不同种属中，甘昔洛韦在肝脏S9组分、血液、RBC和血浆中的水解速率与小肠黏膜中的水解速率并不平行。
前药SC-48334生物利用度的种属差异是由于前药在小肠黏膜中水解速率的种属差异所致。猴是预测人小肠酯酶活性及人相对生物利用度的良好动物模型。
