PURPOSE: PEPT1 mediates the intestinal absorption of many drugs, but its contribution to oral absorption of drugs is still controversial. The objective of this study is to quantitatively evaluate the contribution of PEPT1 to oral absorption of cephalexin, a typical substrate for PEPT1, in rats. MATERIALS AND METHODS: The absorbability of cephalexin via PEPT1 or passive diffusion was assessed in five intestinal segments by utilizing glycyl-proline as a competitive inhibitor by in-situ closed loop method. Absorption kinetics of cephalexin after oral administration was predicted by GI-Transit-Absorption model. RESULTS: Absorbability of cephalexin was segment-dependent, and concentration-dependent in all the segments except for the lower ileum. Intrinsic absorption rate constant via PEPT1 ranged from 0.64 to 4.07 h(-1). The absorption rate constants via passive diffusion ranged from 0.78 to 1.24 h(-1). Plasma concentration-time profile of cephalexin was successfully predicted and the substantial contribution of PEPT1 to the oral absorption was calculated to be from 46% to 60% of total absorption. Simulation study indicated that 83% bioavailability would be expected for cephalexin even though PEPT1 does not function. CONCLUSIONS: PEPT1 substantially contributes to oral absorption of cephalexin, around a half of total absorption. However, the function of PEPT1 can be compensated by passive diffusion for cephalexin.
PURPOSE:PEPT1 mediates the intestinal absorption of many drugs, but its contribution to oral absorption of drugs is still controversial. The objective of this study is to quantitatively evaluate the contribution of PEPT1 to oral absorption of cephalexin, a typical substrate for PEPT1, in rats. MATERIALS AND METHODS: The absorbability of cephalexin via PEPT1 or passive diffusion was assessed in five intestinal segments by utilizing glycyl-proline as a competitive inhibitor by in-situ closed loop method. Absorption kinetics of cephalexin after oral administration was predicted by GI-Transit-Absorption model. RESULTS: Absorbability of cephalexin was segment-dependent, and concentration-dependent in all the segments except for the lower ileum. Intrinsic absorption rate constant via PEPT1 ranged from 0.64 to 4.07 h(-1). The absorption rate constants via passive diffusion ranged from 0.78 to 1.24 h(-1). Plasma concentration-time profile of cephalexin was successfully predicted and the substantial contribution of PEPT1 to the oral absorption was calculated to be from 46% to 60% of total absorption. Simulation study indicated that 83% bioavailability would be expected for cephalexin even though PEPT1 does not function. CONCLUSIONS:PEPT1 substantially contributes to oral absorption of cephalexin, around a half of total absorption. However, the function of PEPT1 can be compensated by passive diffusion for cephalexin.
Authors: Hye-Ryoung Kim; Sung-Won Park; Hee-Jung Cho; Kyung-Ae Chae; Ji-Min Sung; Jin-Suk Kim; Christopher P Landowski; Duxin Sun; A M Abd El-Aty; Gordon L Amidon; Ho-Chul Shin Journal: Pharmacol Res Date: 2007-06-23 Impact factor: 7.658
Authors: Kiyohiko Sugano; Manfred Kansy; Per Artursson; Alex Avdeef; Stefanie Bendels; Li Di; Gerhard F Ecker; Bernard Faller; Holger Fischer; Grégori Gerebtzoff; Hans Lennernaes; Frank Senner Journal: Nat Rev Drug Discov Date: 2010-08 Impact factor: 84.694
Authors: Danny Tsai; Janattul-Ain Jamal; Joshua S Davis; Jeffrey Lipman; Jason A Roberts Journal: Clin Pharmacokinet Date: 2015-03 Impact factor: 6.447