Chan O H, Schmid H L, Stilgenbauer L A, Howson W, Horwell D C, Stewart B H
Pharmacokinetics and Drug Metabolism Department, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
Pharm Res. 1998 Jul;15(7):1012-8. doi: 10.1023/a:1011969808907.
The purpose of this research was to examine a targeted prodrug strategy to increase the absorption of a poorly water-soluble lipophilic compound.
Three water-soluble prodrugs of Cam-4451 were synthesized. The amino acid (Cam-4562, Cam-4580) or phosphate (Cam-5223) ester prodrugs introduced moieties ionized at physiological pH and targeted intestinal brush-border membrane enzymes for reconversion to the parent. Selectivity for reconversion of the three prodrugs was examined in rat intestinal perfusate and brush-border membrane suspensions. Bioavailability of Cam-4451 in rats was evaluated after administering orally as the parent or as prodrugs in a cosolvent vehicle or in methylcellulose.
Cam-5223 was highly selective for reconversion at the brush-border, but was rapidly reconverted in intestinal perfusate. Cam-4562 was not as selective but was more stable in the perfusate, whereas Cam-4580 was neither selective nor stable. Oral bioavailability of Cam-4451 was 14% after dosing as the parent in the cosolvent vehicle, 39% and 46%, respectively, as Cam-4562 and Cam-5223. Oral bioavailability was only 3.6% when the parent was dosed in methylcellulose, whereas the bioavailability was 7-fold higher when dosed as the phosphate prodrug.
Water-soluble prodrugs that target brush-border membrane enzymes for reconversion can be useful in improving drug oral bioavailability.
本研究的目的是考察一种靶向性前药策略，以提高一种水溶性差的亲脂性化合物的吸收。
合成了Cam-4451的三种水溶性前药。氨基酸（Cam-4562、Cam-4580）或磷酸酯（Cam-5223）前药引入了在生理pH值下可离子化的基团，并靶向肠道刷状缘膜酶以重新转化为母体药物。在大鼠肠灌流液和刷状缘膜悬浮液中考察了这三种前药重新转化的选择性。以母体药物或前药的形式在助溶剂或甲基纤维素中口服给药后，评估了Cam-4451在大鼠体内的生物利用度。
Cam-5223在刷状缘具有高度的重新转化选择性，但在肠灌流液中迅速重新转化。Cam-4562的选择性较低，但在灌流液中更稳定，而Cam-4580既没有选择性也不稳定。以母体药物形式在助溶剂中给药后，Cam-4451的口服生物利用度为14%，以Cam-4562和Cam-5223给药时分别为39%和46%。当母体药物以甲基纤维素给药时，口服生物利用度仅为3.6%，而以磷酸前药给药时生物利用度高出7倍。
靶向刷状缘膜酶进行重新转化的水溶性前药可用于提高药物的口服生物利用度。
