L-pyroglutamyl-L-tryptophan derivatives as potential drug carriers. II.: Permeation behaviour and stability in the gastro-intestinal tract.

The in vitro permeation behaviour of L-tryptophan (1). L-pyroglutamic acid (2), L-pyroglutamyl-L-tryptophan (3), and the corresponding ethyl ester derivatives (4, 5 and 6 respectively) was studied to collect the essential informations for oral administration of these molecules. Dipeptides 3 and 6 offer a potentially useful mean to facilitate diffusion across the blood-brain barrier (BBB) and enhance the rate of entry of drug molecules into the central nervous system (CNS). The transfer rate constants (Kd) from simulated gastro-intestinal juices to simulated plasma, throughout artificial wall lipid membranes, were defined. The Kd values suggested that the molecules are absorbed both in gastric and intestinal environments in about comparable amounts. Since peptide bonds are often rapidly broken down by enzymes of most biological fluids the enzymatic hydrolysis characteristics in natural gastro-intestinal environment were studied. While hydrolysis of the ester bond of 6 was about 12%, after 5 h no important hydrolysis was observed for peptide bond of 3 and 6.