title: In vivo and in vitro evaluations of intestinal gabapentin absorption: effect of dose and inhibitors on carrier-mediated transport.
abstract: OBJECTIVE
  Gabapentin exhibits saturable absorption kinetics, however, it remains unclear which transporters that are involved in the intestinal transport of gabapentin. Thus, the aim of the current study was to explore the mechanistic influence of transporters on the intestinal absorption of gabapentin by both in vivo and in vitro investigations
  
  
  METHODS
  Pharmacokinetic parameters were determined following a range of intravenous (5-100 mg/kg) and oral doses (10-200 mg/kg) in rats. Transepithelial transport (50 μM-50 mM) and apical uptake of gabapentin (0.01-50 mM) were investigated in Caco-2 cells. The effect of co-application of the LAT-inhibitor, BCH, and the b(0,+)-substrate, L-lysine, on intestinal transport of gabapentin was evaluated in vivo and in vitro.
  
  
  RESULTS
  Gabapentin showed dose-dependent oral absorption kinetics and dose-independent disposition kinetics. Co-application of BCH inhibited intestinal absorption in vivo and apical uptake in vitro, whereas no effect was observed following co-application of L-lysine.
  
  
  CONCLUSIONS
  The present study shows for the first time that BCH was capable of inhibiting intestinal absorption of gabapentin in vivo. Furthermore, in Caco-2 cell experiments BCH inhibited apical uptake of gabapentin. These findings may imply that a BCH-sensitive transport-system was involved in the apical and possibly the basolateral transport of gabapentin across the intestinal wall.
authors.affiliation: Biologics and Pharmaceutical Science, H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, Denmark.
authors.forename: Malte Selch
authors.initials: MS
authors.lastname: Larsen
authors.forename: Sidsel
authors.initials: S
authors.lastname: Frølund
authors.forename: Martha Kampp
authors.initials: MK
authors.lastname: Nøhr
authors.forename: Carsten Uhd
authors.initials: CU
authors.lastname: Nielsen
authors.forename: Mats
authors.initials: M
authors.lastname: Garmer
authors.forename: Mads
authors.initials: M
authors.lastname: Kreilgaard
authors.forename: René
authors.initials: R
authors.lastname: Holm
mesh_terms: D000284:Administration, Oral; D000588:Amines / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D000598:Amino Acids, Cyclic / Q000494:pharmacology; D000818:Animals; D018938:Caco-2 Cells; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D000077206:Gabapentin; D006801:Humans; D007275:Injections, Intravenous; D007408:Intestinal Absorption / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D049990:Membrane Transport Modulators / Q000494:pharmacology; D026901:Membrane Transport Proteins / Q000009:adverse effects / Q000378:metabolism*; D008954:Models, Biological; D017207:Rats, Sprague-Dawley; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D000588:Amines; D000598:Amino Acids, Cyclic; D003509:Cyclohexanecarboxylic Acids; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; C006504:2-aminobicyclo(2,2,1)heptane-2-carboxylic acid; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin