Quantitative evaluation of PEPT1 contribution to oral absorption of cephalexin in rats.
OBJECTIVE
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.


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.
Hironaka
Takanori
T
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Okayama, 700-8530, Japan.
Itokawa
Shota
S
Ogawara
Ken-ichi
K
Higaki
Kazutaka
K
Kimura
Toshikiro
T
D000465:Algorithms; D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D015153:Blotting, Western; D002506:Cephalexin / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D003198:Computer Simulation; D004058:Diffusion; D004151:Dipeptides / Q000494:pharmacology; D007275:Injections, Intravenous; D007408:Intestinal Absorption / Q000502:physiology; D007441:Intubation, Gastrointestinal; D008297:Male; D000074011:Peptide Transporter 1; D011237:Predictive Value of Tests; D051381:Rats; D017208:Rats, Wistar; D027981:Symporters / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D004151:Dipeptides; D000074011:Peptide Transporter 1; C489940:Slc15a1 protein, rat; D027981:Symporters; C015248:glycylproline; D002506:Cephalexin
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