title: Intestinal absorption of the antiepileptic drug substance vigabatrin is altered by infant formula in vitro and in vivo.
abstract: Vigabatrin is an antiepileptic drug substance mainly used in pediatric treatment of infantile spasms. The main source of nutrition for infants is breast milk and/or infant formula. Our hypothesis was that infant formula may affect the intestinal absorption of vigabatrin. The aim was therefore to investigate the potential effect of coadministration of infant formula with vigabatrin on the oral absorption in vitro and in vivo. The effect of vigabatrin given with an infant formula on the oral uptake and transepithelial transport was investigated in vitro in Caco-2 cells. In vivo effects of infant formula and selected amino acids on the pharmacokinetic profile of vigabatrin was investigated after oral coadministration to male Sprague-Dawley rats using acetaminophen as a marker for gastric emptying. The presence of infant formula significantly reduced the uptake rate and permeability of vigabatrin in Caco-2 cells. Oral coadministration of vigabatrin and infant formula significantly reduced C max and prolonged t max of vigabatrin absorption. Ligands for the proton-coupled amino acid transporter PAT1, sarcosine, and proline/l-tryptophan had similar effects on the pharmacokinetic profile of vigabatrin. The infant formula decreased the rate of gastric emptying. Here we provide experimental evidence for an in vivo role of PAT1 in the intestinal absorption of vigabatrin. The effect of infant formula on the oral absorption of vigabatrin was found to be due to delayed gastric emptying, however, it seems reasonable that infant formula may also directly affect the intestinal absorption rate of vigabatrin possibly via PAT1.
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen DK-2100, Copenhagen, Denmark.
authors.forename: Martha Kampp
authors.initials: MK
authors.lastname: Nøhr
authors.affiliation: Department of Bioanalysis, H. Lundbeck A/S DK-2500, Valby, Denmark.
authors.forename: Zia I
authors.initials: ZI
authors.lastname: Thale
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen DK-2100, Copenhagen, Denmark.
authors.forename: Birger
authors.initials: B
authors.lastname: Brodin
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen DK-2100, Copenhagen, Denmark.
authors.forename: Steen H
authors.initials: SH
authors.lastname: Hansen
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen DK-2100, Copenhagen, Denmark ; Biologics and Pharmaceutical Science, H. Lundbeck A/S DK-2500, Valby, Denmark.
authors.forename: René
authors.initials: R
authors.lastname: Holm
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen DK-2100, Copenhagen, Denmark.
authors.forename: Carsten Uhd
authors.initials: CU
authors.lastname: Nielsen
keywords: Caco-2 cells; LYAAT1; PAT1; SLC36A1; Sprague–Dawley rats; Vigabatrin; drug absorption; infant formula; pharmacokinetic