title: Rectal absorption of vigabatrin, a substrate of the proton coupled amino acid transporter (PAT1, Slc36a1), in rats.
abstract: OBJECTIVE
  To investigate the rectal absorption of vigabatrin in rats, based on the hypothesis that PAT1 (Slc36a1) is involved.
  
  
  METHODS
  Male Sprague-Dawley rats were dosed rectally with five different gels, varying in buffer capacity, the amount of vigabatrin, and co-administration of proline or tryptophan. Western blotting was used to detect rPAT1 in rat rectal epithelium. X. Laevis oocytes were injected with SLC36A1 cRNA for the expression of hPAT1, prior to two-electrode voltage clamp measurements.
  
  
  RESULTS
  rPAT1 protein was present in rat rectal epithelium. Approximately 7%-9% of a 1 mg/kg vigabatrin dose was absorbed after rectal administration, regardless of the formulation used. Increasing the dose of vigabatrin 10-fold decreased the absolute bioavailability to 4.2%. Co-administration of proline or tryptophan changed the pharmacokinetic profile, indicating a role of PAT1 in the rectal absorption of vigabatrin. Transport of vigabatrin via hPAT1 expressed in X. Laevis oocytes had a K(m) of 5.2 ± 0.6 mM and was almost completely inhibited by tryptophan.
  
  
  CONCLUSIONS
  Although vigabatrin is a PAT1 substrate and the rPAT1 protein is expressed in the rectum epithelium, vigabatrin has low rectal absorption in rats.
authors.affiliation: Preformulation, H.Lundbeck A/S, Ottiliavej 9, DK-2500, Valby, Denmark.
authors.forename: René
authors.initials: R
authors.lastname: Holm
authors.forename: Morten A
authors.initials: MA
authors.lastname: Kall
authors.forename: Sidsel
authors.initials: S
authors.lastname: Frølund
authors.forename: Andreas L
authors.initials: AL
authors.lastname: Nielsen
authors.forename: Anne
authors.initials: A
authors.lastname: Jensen
authors.forename: Mie Larsen
authors.initials: ML
authors.lastname: Broberg
authors.forename: Carsten Uhd
authors.initials: CU
authors.lastname: Nielsen
mesh_terms: D000042:Absorption; D000285:Administration, Rectal; D026905:Amino Acid Transport Systems / Q000037:antagonists & inhibitors / Q000378:metabolism*; D026921:Amino Acid Transport Systems, Neutral / Q000378:metabolism*; D000818:Animals; D001682:Biological Availability; D001692:Biological Transport / Q000502:physiology; D018938:Caco-2 Cells; D004848:Epithelium / Q000378:metabolism; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009865:Oocytes / Q000378:metabolism; D011392:Proline / Q000378:metabolism; D011522:Protons; D051381:Rats; D017207:Rats, Sprague-Dawley; D012007:Rectum / Q000378:metabolism*; D027981:Symporters / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014364:Tryptophan / Q000378:metabolism; D020888:Vigabatrin / Q000493:pharmacokinetics* / Q000494:pharmacology; D014982:Xenopus laevis
chemical_list: D026905:Amino Acid Transport Systems; D026921:Amino Acid Transport Systems, Neutral; D011522:Protons; C475905:SLC36A1 protein, human; C493537:Slc36a1 protein, rat; D027981:Symporters; D014364:Tryptophan; D011392:Proline; D020888:Vigabatrin