Aungst B J, Saitoh H
Dupont Merck Research Laboratories, Wilmington, Delaware 19880-0400, USA.
Pharm Res. 1996 Jan;13(1):114-9. doi: 10.1023/a:1016093704095.
The intestinal absorption of DMP 728, a cyclic peptide fibrinogen antagonist, was examined with the goals of identifying the cause(s) of its low oral bioavailability and understanding the mechanisms of its intestinal transport.
In vitro partitioning, metabolism, and permeation through rat intestinal segments were evaluated.
DMP 728 had low lipophilicity and low intestinal permeation rates relative to model compounds. In addition, DMP 728 in vitro intestinal permeation in the secretory direction greatly exceeded transport in the absorptive direction. The secretory transport was saturable, glucose-dependent, and was inhibited by verapamil and by a monoclonal antibody to P-glycoprotein. DMP 728 likewise inhibited the secondary transport of verapamil. Mucosal-to-serosal permeation rates increased in going from the proximal to distal intestinal sites, but were lower than serosal-to-mucosal permeation rates for each site.
Net secretory transport and low lipophilicity are the major barriers to absorption of DMP 728.
研究环肽纤维蛋白原拮抗剂DMP 728的肠道吸收情况，以确定其口服生物利用度低的原因，并了解其肠道转运机制。
评估DMP 728在大鼠肠段的体外分配、代谢及渗透情况。
相对于模型化合物，DMP 728的亲脂性较低，肠道渗透速率也较低。此外，DMP 728在体外肠道中的分泌方向渗透大大超过吸收方向的转运。分泌性转运具有饱和性、葡萄糖依赖性，且受维拉帕米和P-糖蛋白单克隆抗体抑制。DMP 728同样抑制维拉帕米的二次转运。从近端肠段到远端肠段，黏膜到浆膜的渗透速率增加，但每个部位的浆膜到黏膜的渗透速率均更高。
净分泌性转运和低亲脂性是DMP 728吸收的主要障碍。
