Nutrient interactions affecting the intestinal absorption of two antiepileptic drugs: Phenytoin and gabapentin.

Abstract

The potential for dissolution or membrane permeability to limit the rate of drug absorption varies with the physicochemical properties of the compound in question. It was the goal of this research to determine the degree to which nutrients influence these limits to the absorption of antiepileptic drugs (AEDs) and the mechanism(s) responsible. In the case of phenytoin (PHT), a poorly soluble AED $\rm(31\mu g/ml),$ fed-state effects have been documented which suggest that either a standard meal or individual nutrients (proteins and lipids) are capable of increasing the drug's intestinal absorption in vivo. Cholecystokinin (CCK) is an endocrine hormone released in the upper small intestine in response to these nutrients. CCK is responsible for regulating gall bladder and pancreatic output, as well as gastric emptying. It is hypothesized that lipid coadministration will enhance PHT absorption by increasing the extent of dissolution within gastrointestinal residence time. MK-329, a benzodiazepine CCK antagonist, inhibits bile salt release. Therefore, pretreatment with MK-329 is expected to inhibit this fed-state effect. Results in dogs indicated that oral lipids increased phenytoin blood levels, but antagonism of this effect by MK-329 was not complete. Gabapentin (GBP), an antiepileptic amino acid analogue, exhibits high aqueous solubility $({>}100$ mg/ml), but capacity-limited membrane permeability. Based on GBP's amino acid-like structure and previous in vitro/in situ data, transport by the system L amino acid transporter in the rat small intestine was investigated. In vitro studies in jejunal tissue showed no change in gabapentin or isobutyl gaba (a structurally similar AED) permeability in the presence of the system L amino acids L-leucine and L-phenylalanine. Glycine, a system A substrate, increased isobutyl gaba permeability three fold, but did not produce a change in gabapentin permeability. Based on GBP's low molecular weight (171 Da), paracellular transport in the small intestine was studied. Monosaccharide coadministration was utilized to promote GBP absorption via solvent drag through tight junctions. Results in dogs indicated that while amino acids did not significantly decrease GBP blood levels in vivo, the monosaccharides produced increases in AUC versus control blood levels that were statistically higher (p $<$ 0.02). The in vitro and in vivo results suggest that the paracellular route was the more dominant of the two transport pathways examined.