title: The proton-coupled oligopeptide transporter 1 plays a major role in the intestinal permeability and absorption of 5-aminolevulinic acid.
abstract: OBJECTIVE
  5-Aminolevulinic acid (5-ALA) has been widely used in photodynamic therapy and immunofluorescence of tumours. In the present study, the intestinal permeability and oral pharmacokinetics of 5-ALA were evaluated to probe the contribution of the proton-coupled oligopeptide transporter 1 (PEPT1) to the oral absorption and systemic exposure of this substrate.
  
  
  METHODS
  In situ single-pass intestinal perfusions and in vivo oral pharmacokinetic studies were performed in wildtype and Pept1 knockout mice. Perfusion studies were performed as a function of concentration dependence, specificity and permeability of 5-ALA in different intestinal segments. Pharmacokinetic studies were performed after 0.2 and 2.0 μmoL·g(-1) doses of 5-ALA.
  
  
  RESULTS
  The permeability of 5-ALA was substantial in duodenal, jejunal and ileal regions of wildtype mice, but the residual permeability of 5-ALA in the small intestine from Pept1 knockout mice was only about 10% of that in wildtype animals. The permeability of 5-ALA in jejunum was specific for PEPT1 with no apparent contribution of other transporters, including the proton-coupled amino acid transporter 1 (PAT1). After oral dosing, the systemic exposure of 5-ALA was reduced by about twofold during PEPT1 ablation, and the pharmacokinetics were dose-proportional after the 0.2 and 2.0 µmol·g(-1) doses. PEPT1 had a minor effect on the disposition and peripheral tissue distribution of 5-ALA.
  
  
  CONCLUSIONS
  Our findings suggested a major role of PEPT1 in the intestinal permeability and oral absorption of 5-ALA. In contrast, another proton-coupled transporter, PAT1, appeared to play a limited role, at best.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Yehua
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Smith
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D026905:Amino Acid Transport Systems / Q000502:physiology; D000622:Aminolevulinic Acid / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D007408:Intestinal Absorption / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000074011:Peptide Transporter 1; D010539:Permeability; D027981:Symporters / Q000235:genetics / Q000502:physiology*; D014018:Tissue Distribution / Q000502:physiology
chemical_list: D026905:Amino Acid Transport Systems; D000074011:Peptide Transporter 1; C489941:Slc15a1 protein, mouse; C483904:Slc36a1 protein, mouse; D027981:Symporters; D000622:Aminolevulinic Acid