L-PYROGLUTAMYL-L-TRYPTOPHAN DERIVATIVES AS POTENTIAL-DRUG CARRIERS .2. PERMEATION BEHAVIOR AND STABILITY IN THE GASTROINTESTINAL-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 th e essential informations for oral administration of these molecules. D ipeptides 3 and 6 offer a potentially useful mean to facilitate diffus ion 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 (K-d) from simulated gastro-intestinal juices to simul ated plasma, throughout artificial wall lipid membranes, were defined. The K-d values suggested that the molecules are absorbed both in gast ric and intestinal environments in about comparable amounts. Since pep tide bonds are often rapidly broken down by enzymes of most biological fluids the enzymatic hydrolysis characteristics in natural gastro-int estinal environment were studied. While hydrolysis of the ester bond o f 6 was about 12%, after 5 h no important hydrolysis was observed for peptide bond of 3 and 6.