INTESTINAL-ABSORPTION STUDIES ON PEPTIDE MIMETIC ALPHA-METHYLDOPA PRODRUGS

Two dipeptide mimetic prodrugs, 1 and 2, and two tripeptide mimetic pr odrugs, 3 and 4, of L-alpha-methyldopa were evaluated for intestinal a bsorption by in-situ single-pass rat jejunal perfusion studies and by in-vitro uptake experiments in brush-border membrane vesicles (BBMVs) prepared from rat intestine. In the perfusion studies, compound 1 demo nstrated a 3.5-fold increase in permeability (P-m = 2.27) as compared with that of alpha-methyldopa (P-m = 0.65), indicating that this pro drug was better absorbed in the intestine than its parent drug. Other prodrugs showed no significant improvement in intestinal permeability. The results correlated with the results of BBMV uptake studies. In th e presence of an inward proton gradient, compound 1 showed Michaelis-M enton saturable kinetics of BBMV uptake with a low value of K-m (0.06 +/- 0.13 mM) and a high value of V-max/K-m (36.38 nmol (mg protein)(-1 )/30 s mM(-1)) at a low concentration range and a linear uptake at hig h concentrations with K-d = 0.14 +/- 0.02 mM. Compounds 2 and 3 were m ainly taken up in BBMVs via passive diffusion. Compound 4 was taken up in BBMVs basically via the carrier-mediated transport system, while t he rate of uptake was much lower than that of compound 1. The uptake o f compounds 1 and 4 was significantly inhibited by dipeptides L-Gly-L- Pro and L-Gly-L-Phe, and cephradine, a beta-lactam known to be transpo rted via the dipeptide carrier system, indicating that both compounds were taken up in BBMVs via the H+-coupled dipeptide-mediated transport system. In contrast to the complicated uptake profile of alpha-methyl dopa, the higher rate of BBMV uptake with less variation demonstrated on compound 1 suggested that the attached nonessential amino acid moie ty, D-phenylglycine, is a feasible delivery tool in carrying the paren t drug through the intestine.