title: Is oral absorption of vigabatrin carrier-mediated?
abstract: The aim of the study was to investigate the intestinal transport mechanisms responsible for vigabatrin absorption in rats by developing a population pharmacokinetic (PK) model of vigabatrin oral absorption. The PK model was used to investigate whether vigabatrin absorption was carrier-mediated and if the proton-coupled amino acid transporter 1 (PAT1) was involved in the absorption processes. Vigabatrin (0.3-300mg/kg) was administered orally or intravenously to Sprague Dawley rats in the absence or presence of PAT1-ligands l-proline, l-tryptophan or sarcosine. The PK profiles of vigabatrin were described by mechanistic non-linear mixed effects modelling, evaluating PAT1-ligands as covariates on the PK parameters with a full covariate modelling approach. The oral absorption of vigabatrin was adequately described by a Michaelis-Menten type saturable absorption. Using a Michaelis constant of 32.8mM, the model estimated a maximal oral absorption rate (Vmax) of 64.6mmol/min and dose-dependent bioavailability with a maximum of 60.9%. Bioavailability was 58.5-60.8% at 0.3-30mg/kg doses, but decreased to 46.8% at 300mg/kg. Changes in oral vigabatrin PK after co-administration with PAT1-ligands was explained by significant increases in the apparent Michaelis constant. Based on the mechanistic model, a high capacity low affinity carrier is proposed to be involved in intestinal vigabatrin absorption. PAT1-ligands increased the Michaelis constant of vigabatrin after oral co-administration indicating that this carrier could be PAT1.
authors.affiliation: Department of Pharmacy, University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors.forename: M K
authors.initials: MK
authors.lastname: Nøhr
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors.forename: R V
authors.initials: RV
authors.lastname: Juul
authors.affiliation: Department of Bioanalysis, H. Lundbeck A/S, DK-2500 Valby, Denmark.
authors.forename: Z I
authors.initials: ZI
authors.lastname: Thale
authors.affiliation: Department of Pharmacy, University of Copenhagen, DK-2100 Copenhagen, Denmark; Biologics and Pharmaceutical Science, H. Lundbeck A/S, DK-2500 Valby, Denmark.
authors.forename: R
authors.initials: R
authors.lastname: Holm
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, DK-2100 Copenhagen, Denmark. Electronic address: mads.kreilgaard@sund.ku.dk.
authors.forename: M
authors.initials: M
authors.lastname: Kreilgaard
authors.affiliation: Department of Pharmacy, University of Copenhagen, DK-2100 Copenhagen, Denmark. Electronic address: carsten.uhdnielsen@sund.ku.dk.
authors.forename: C U
authors.initials: CU
authors.lastname: Nielsen
mesh_terms: D000284:Administration, Oral; D026921:Amino Acid Transport Systems, Neutral / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D007408:Intestinal Absorption; D008297:Male; D008954:Models, Biological; D011392:Proline / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D012521:Sarcosine / Q000494:pharmacology; D027981:Symporters / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014364:Tryptophan / Q000494:pharmacology; D020888:Vigabatrin / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D026921:Amino Acid Transport Systems, Neutral; C493537:Slc36a1 protein, rat; D027981:Symporters; D014364:Tryptophan; D011392:Proline; D020888:Vigabatrin; D012521:Sarcosine
keywords: Drug absorption; PAT1; Population based pharmacokinetics; Rat; Slc36a1; Vigabatrin