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.

Keywords: Caco-2 cells; LYAAT1; PAT1; SLC36A1; Sprague–Dawley rats; Vigabatrin; drug absorption; infant formula; pharmacokinetic.

Figure 1

Apparent permeability of transepithelial vigabatrin (1.0 mmol/L) transport across Caco-2 cell monolayers in the presence or absence of infant formula. (A) The permeability (P_app) was measured in the presence or absence of 35.0 mmol/L Trp, infant formula or 20 mg mL⁻¹ (151.4 mmol/L) Gly-Gly or Gly-Sar (136.9 mmol/L). (B) Vigabatrin permeability in the absence or presence of 20 mg mL⁻¹ BCH (128.9 mmol/L) or Ile (152.5 mmol/L). Permeability was measured across Caco-2 cells cultured for 20 days on transwell filters. Dark gray control is the vigabatrin permeability in HBSS buffer, light gray columns are in NaCl-reduced HBSS. Columns represent mean ± SEM of permeability measured in 3–4 passages. ANOVA followed by Dunnett's multiple comparison test. *Significant difference from both controls (P < 0.05).

Figure 2

The plasma concentration time profile of vigabatrin after oral administration of 1.0 or 10.0 mg kg⁻¹ vigabatrin to male Sprague–Dawley rats. (A) The rats received solutions containing 1.0 mg kg⁻¹ vigabatrin alone or coadministered with 1500 mg kg⁻¹ infant formula or low fat infant formula. (B) The rats received solutions containing 1.0 mg kg⁻¹ vigabatrin alone or coadministered with 100 mg kg⁻¹ (86.9 mmol/L) Pro and (49.0 mmol/L) Trp, 200 mg kg⁻¹ (224.5 mmol/L) Sar or (128.9 mmol/L) BCH. (C) The rats received solutions containing 10.0 mg kg⁻¹ vigabatrin alone or coadministered with 1500 mg kg⁻¹ infant formula or low fat infant formula or 200 mg kg⁻¹ Sar. Data points represent mean ± SEM from six different animals.

Figure 3

The plasma concentration time profile of acetaminophen after oral administration of 120 mg kg⁻¹ acetaminophen to male Sprague–Dawley rats. The rats received solutions containing 120 mg kg⁻¹ acetaminophen and 10.0 mg kg⁻¹ vigabatrin alone or coadministered with 1500 mg kg⁻¹ infant formula, low fat infant formula or 200 mg kg⁻¹ Sar. Data points represent mean ± SEM from six different animals.

Figure 4

(A) Deconvolution profiles of acetaminophen absorption after oral administration to male Sprague–Dawley rats. Deconvolution profiles of 120 mg kg⁻¹ acetaminophen alone or coadministered with 1500 mg kg⁻¹ infant formula, low fat infant formula or 200 mg kg⁻¹ Sar. Data represents mean ± SEM from five to six different animals. The data were fitted to equation (8) to estimate the absorption rate constant for acetaminophen (k_empty). (B) Distribution of k_empty values of acetaminophen estimated from the individual animals. ANOVA followed by Dunnett's multiple comparison test. #Significant difference from control (P < 0.05).