title: Quantitative evaluation of PEPT1 contribution to oral absorption of cephalexin in rats.
abstract: 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.
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Okayama, 700-8530, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Hironaka
authors.forename: Shota
authors.initials: S
authors.lastname: Itokawa
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Ogawara
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Higaki
authors.forename: Toshikiro
authors.initials: T
authors.lastname: Kimura
mesh_terms: 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*
chemical_list: D000900:Anti-Bacterial Agents; D004151:Dipeptides; D000074011:Peptide Transporter 1; C489940:Slc15a1 protein, rat; D027981:Symporters; C015248:glycylproline; D002506:Cephalexin
references.citation: J Pharm Pharmacol. 1979 Oct;31(10):718-20
references.pmid: 41054
references.citation: Br J Pharmacol. 1994 Nov;113(3):1050-6
references.pmid: 7858848
references.citation: J Pharm Pharmacol. 1997 Aug;49(8):796-801
references.pmid: 9379359
references.citation: Biochim Biophys Acta. 1978 Jan 4;506(1):136-54
references.pmid: 620021
references.citation: J Biol Chem. 1997 Mar 21;272(12):7777-85
references.pmid: 9065440
references.citation: Pharm Res. 1988 Oct;5(10):645-50
references.pmid: 3244617
references.citation: J Control Release. 2003 Jan 17;86(2-3):305-13
references.pmid: 12526826
references.citation: Proc Assoc Am Physicians. 1998 Jul-Aug;110(4):361-8
references.pmid: 9686684
references.citation: J Control Release. 2007 Jun 4;119(2):222-8
references.pmid: 17442444
references.citation: Pharm Res. 2000 Jan;17(1):15-20
references.pmid: 10714602
references.citation: Biochem Pharmacol. 1984 Nov 1;33(21):3345-52
references.pmid: 6497897
references.citation: Eur J Pharm Sci. 2006 Apr;27(5):487-500
references.pmid: 16376527
references.citation: J Pharmacol Exp Ther. 1997 Jun;281(3):1415-21
references.pmid: 9190878
references.citation: J Pharmacokinet Pharmacodyn. 2001 Apr;28(2):109-28
references.pmid: 11381566
references.citation: Eur J Biochem. 1999 Dec;266(2):502-8
references.pmid: 10561591
references.citation: Pharm Res. 1988 Oct;5(10):651-4
references.pmid: 3244618
references.citation: Nature. 1970 Aug 15;227(5259):680-5
references.pmid: 5432063
references.citation: J Pharmacol Exp Ther. 2005 Jan;312(1):248-55
references.pmid: 15466248
references.citation: Biochim Biophys Acta. 1976 May 21;433(3):509-19
references.pmid: 179591
references.citation: J Pharm Pharmacol. 1997 Apr;49(4):450-7
references.pmid: 9232547
references.citation: Biochem Biophys Res Commun. 1995 Nov 2;216(1):249-57
references.pmid: 7488096
references.citation: Jpn J Antibiot. 1977 Aug;30(8):631-8
references.pmid: 909151
references.citation: Pharm Res. 1996 Jul;13(7):963-77
references.pmid: 8842032
references.citation: Pharm Res. 1999 Jan;16(1):55-61
references.pmid: 9950279
references.citation: Biol Pharm Bull. 2002 Feb;25(2):149-64
references.pmid: 11853157
references.citation: J Pharmacobiodyn. 1986 Apr;9(4):368-74
references.pmid: 3735059
references.citation: Chem Pharm Bull (Tokyo). 1977 Apr;25(4):675-9
references.pmid: 880710
references.citation: Pharm Res. 1993 Jul;10(7):1093-5
references.pmid: 8378254
references.citation: J Pharm Pharmacol. 1980 Jun;32(6):394-8
references.pmid: 6106670
references.citation: J Pharmacol Exp Ther. 2001 Nov;299(2):575-82
references.pmid: 11602669
references.citation: Am J Physiol Gastrointest Liver Physiol. 2002 Apr;282(4):G617-23
references.pmid: 11897620
references.citation: Yakugaku Zasshi. 1994 Apr;114(4):233-40
references.pmid: 8201544
references.citation: Am J Physiol Gastrointest Liver Physiol. 2002 Jul;283(1):G57-64
references.pmid: 12065292
references.citation: J Pharmacol Exp Ther. 1957 Aug;120(4):528-39
references.pmid: 13476377
references.citation: Biopharm Drug Dispos. 1995 Jul;16(5):351-80
references.pmid: 8527686
references.citation: Biochem Biophys Res Commun. 1988 Sep 15;155(2):1082-7
references.pmid: 3421959
references.citation: Pharm Res. 2002 Oct;19(10):1417-23
references.pmid: 12425457
references.citation: Biochem Pharmacol. 1983 Feb 15;32(4):621-6
references.pmid: 6830625
references.citation: Histochem J. 1999 Mar;31(3):169-74
references.pmid: 10421416
references.citation: Annu Rev Nutr. 1996;16:99-119
references.pmid: 8839921
references.citation: Biol Pharm Bull. 2006 May;29(5):997-1005
references.pmid: 16651734
references.citation: J Vet Pharmacol Ther. 1998 Oct;21(5):418-20
references.pmid: 9811445
references.citation: Pharm Res. 1999 Sep;16(9):1331-43
references.pmid: 10496647
references.citation: Am J Physiol. 1999 Apr;276(4):C821-6
references.pmid: 10199812
references.citation: Biochem Pharmacol. 2005 Dec 5;70(12):1756-63
references.pmid: 16259962
references.citation: Int J Pharm. 2002 Feb 21;233(1-2):179-90
references.pmid: 11897422
references.citation: J Nutr. 2004 Sep;134(9):2211-5
references.pmid: 15333706
references.citation: J Pharmacol Exp Ther. 2003 Nov;307(2):626-32
references.pmid: 12970381
references.citation: Metabolism. 1999 Jun;48(6):681-4
references.pmid: 10381139
references.citation: Chem Pharm Bull (Tokyo). 1970 May;18(5):1034-9
references.pmid: 5419238
references.citation: J Pharmacol Exp Ther. 2000 Aug;294(2):466-72
references.pmid: 10900220
references.citation: Int J Pharm. 2000 Dec 4;210(1-2):15-27
references.pmid: 11163984
references.citation: FEBS Lett. 1996 Sep 30;394(2):196-200
references.pmid: 8843163
references.citation: Appl Environ Microbiol. 1992 Dec;58(12):3954-8
references.pmid: 1476438
references.citation: AAPS PharmSci. 2001;3(1):E9
references.pmid: 11741260
references.citation: Pharmacol Res. 2007 Sep;56(3):224-36
references.pmid: 17681807
references.citation: J Pharm Pharmacol. 1990 May;42(5):314-8
references.pmid: 1976777
references.citation: J Physiol. 1998 Mar 15;507 ( Pt 3):697-706
references.pmid: 9508831
references.citation: Drug Metab Dispos. 2000 May;28(5):577-81
references.pmid: 10772638
references.citation: J Pharmacobiodyn. 1981 Nov;4(11):879-85
references.pmid: 7328489
references.citation: J Pharm Sci. 1998 Sep;87(9):1081-5
references.pmid: 9724558