A NONAQUEOUS PARTITIONING SYSTEM FOR PREDICTING THE ORAL ABSORPTION POTENTIAL OF PEPTIDES

In the search for a better model of the rate limiting processes in pep tide transport we studied the partitioning of solutes between heptane and ethylene glycol. Methods for determining the log partition coeffic ient (logP(H/G)) in this solvent system were developed and the reprodu cibility and ruggedness of such determinations were assessed. The part ition coefficients in this system were found to correlate (r(2) = 0.86 , n = 11) with the permeability coefficients for a group of model pept ides. To understand the physical forces governing this partitioning pr ocess, the influence of four solvatochromic parameters: hydrogen bond donor strength (alpha) hydrogen bond acceptor strength (beta), polarit y (pi), and molecular volume (V-I), was evaluated for a set of 20 ben zene derivatives. Multiple regression analysis revealed that the solut e hydrogen bonding parameters, especially alpha, were the most importa nt determinants. Molecular volume of the solute was about half as infl uential compared with partitioning systems in which water is the polar phase. These results suggest that the requirement for hydrogen bond b reaking is the principal deterrent to peptide transport and that logP( H/G) is useful in predicting permeance.