title: In vivo absorption and disposition of cefadroxil after escalating oral doses in wild-type and PepT1 knockout mice.
abstract: OBJECTIVE
  To determine the effect of PepT1 on the absorption and disposition of cefadroxil, including the potential for saturable intestinal uptake, after escalating oral doses of drug.
  
  
  METHODS
  The absorption and disposition kinetics of [3H]cefadroxil were determined in wild-type and PepT1 knockout mice after 44.5, 89.1, 178, and 356 nmol/g oral doses of drug. The pharmacokinetics of [3H]cefadroxil were also determined in both genotypes after 44.5 nmol/g intravenous bolus doses.
  
  
  RESULTS
  PepT1 deletion reduced the area under the plasma concentration-time profile (AUC0-120) of cefadroxil by 10-fold, the maximum plasma concentration (Cmax) by 17.5-fold, and increased the time to reach a maximum plasma concentration (Tmax) by 3-fold. There was no evidence of nonlinear intestinal absorption since AUC0-120 and Cmax values changed in a dose-proportional manner. Moreover, the pharmacokinetics of cefadroxil were not different between genotypes after intravenous bolus doses, indicating that PepT1 did not affect drug disposition. Finally, no differences were observed in the peripheral tissue distribution of cefadroxil (i.e., outside gastrointestinal tract) once these tissues were corrected for differences in perfusing blood concentrations.
  
  
  CONCLUSIONS
  The findings demonstrate convincingly the critical role of intestinal PepT1 in both the rate and extent of oral administration for cefadroxil and potentially other aminocephalosporin drugs.
authors: Maria M
authors: MM
authors: Posada
authors: David E
authors: DE
authors: Smith
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology*; D002434:Cefadroxil / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D017353:Gene Deletion; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000074011:Peptide Transporter 1; D027981:Symporters / Q000235:genetics* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D000074011:Peptide Transporter 1; C489941:Slc15a1 protein, mouse; D027981:Symporters; D002434:Cefadroxil
references: Nat Rev Drug Discov. 2010 Mar;9(3):215-36
references: 20190787
references: J Pharm Pharmacol. 2008 May;60(5):543-85
references: 18416933
references: Eur J Clin Pharmacol. 1980 Nov;18(6):505-9
references: 7461017
references: Drug Metab Dispos. 2010 Oct;38(10):1740-6
references: 20660104
references: J Pharm Sci. 1981 Jul;70(7):768-72
references: 7264924
references: Drug Metab Dispos. 2011 Dec;39(12):2250-7
references: 21880829
references: Trends Pharmacol Sci. 2002 Sep;23(9):434-40
references: 12237156
references: Drug Metab Dispos. 1993 Mar-Apr;21(2):215-7
references: 8097688
references: Eur J Clin Pharmacol. 1991;41(2):179-83
references: 1743250
references: Pharm Res. 2013 Apr;30(4):1017-25
references: 23224978
references: Biopharm Drug Dispos. 1996 May;17(4):319-30
references: 8743403
references: J Pharm Pharmacol. 2008 Jan;60(1):63-70
references: 18088506
references: Pharm Res. 1999 Jan;16(1):55-61
references: 9950279
references: Drugs. 1986;32 Suppl 3:1-16
references: 3542485
references: Mol Pharm. 2008 Nov-Dec;5(6):1122-30
references: 19434858
references: Am J Physiol. 1999 May;276(5):F658-65
references: 10330047
references: Biochem J. 2001 May 15;356(Pt 1):53-60
references: 11336635
references: Pharm Res. 1998 Aug;15(8):1154-9
references: 9706043
references: Lab Invest. 2002 Feb;82(2):193-201
references: 11850532
references: Antimicrob Agents Chemother. 1977 Feb;11(2):324-30
references: 848939
references: Antimicrob Agents Chemother. 1982 Feb;21(2):320-2
references: 7073267
references: Biochem Pharmacol. 2010 Feb 1;79(3):455-62
references: 19735648
references: Drug Metab Dispos. 2007 Jul;35(7):1209-16
references: 17452417
references: Mol Aspects Med. 2013 Apr-Jun;34(2-3):323-36
references: 23506874
references: J Pharmacol Exp Ther. 2005 Oct;315(1):240-7
references: 15987832
references: Drug Metab Dispos. 2013 Mar;41(3):608-14
references: 23264448
references: Mol Pharm. 2004 Jul-Aug;1(4):248-56
references: 15981584
references: Int J Clin Pharmacol Ther Toxicol. 1982 Feb;20(2):73-7
references: 7061182
references: J Biol Chem. 1997 Apr 11;272(15):10205-11
references: 9092568
references: Drug Metab Dispos. 2012 Mar;40(3):515-21
references: 22166395
references: J Pharm Pharmacol. 1989 Mar;41(3):179-85
references: 2568445
references: Xenobiotica. 2008 Jul;38(7-8):1022-42
references: 18668438
references: Trends Pharmacol Sci. 2008 Apr;29(4):200-7
references: 18353444
references: Pharm Res. 2012 Feb;29(2):535-45
references: 21904935