Dipeptide uptake enhances the absorption of 3-substituted GABA derivatives by trans-stimulation of amino acid exchangers

PEPT1-mediated uptake of dipeptides has been shown to facilitate enhanced absorption of amino acids by system b0,+ in Caco-2 cells. It is unknown whether the same interaction can be applied towards improving the absorption of amino acid-like drugs. The 3-substituted GABA-derivatives, gabapentin and baclofen, share similar structures to leucine, phenylalanine and arginine and are transported by the amino acid exchangers, systems b 0,+ and B0, respectively. We hypothesized that dipeptide uptake through PEPT1 was capable of enhancing the oral permeability and affect the pharmacokinetics of both gabapentin and baclofen through the trans-stimulation of b0,+ and B0 exchange. Our main objectives were (1) to assess the extent to which dipeptide loading influences the permeability and pharmacokinetics of the GABA-derivatives, and (2) to explore the mechanism underlying the interaction between PEPT1 and systems b0,+ and B0. The in situ rat intestinal perfusion and in vivo rat models were used in our investigations. The results showed a significant improvement in gabapentin and baclofen effective permeability as well as an increase in gabapentin Cmax and AUC following intestinal loading with the dipeptide glycylglutamate. Based on our findings, the following mechanism has been proposed: (i) PEPT1 mediates the uptake of glycylglutamate, following which it undergoes intracellular hydrolysis to the constituent amino acids, glycine and glutamate; (ii) the latter amino acid is then converted to glutamine, which provides the driving force for the trans-stimulated absorption of gabapentin and baclofen via b0,+ and B0 exchange, respectively. In conclusion, our studies demonstrate, for the first time, a direct relationship between the PEPT1-mediated uptake of a dipeptide and the trans-stimulated uptake of amino acid-like drugs in both in situ and in vivo models. The present work uncovered one mechanism by which food and drug can interact, and provides insight into the food effect and its implications on drug pharmacokinetics and therapeutic response.