Relationships between human intestinal absorption and polar interactions drug/phospholipids estimated by IAM–HPLC.

Abstract

Phospholipid affinity indexes (logkWIAM) for 15 structurally non-related basic, acidic, ampholytic, and neutral drugs were measured by HPLC on two different phospholipid stationary phases (immobilized artificial membrane – IAM). According to a method we previously proposed, polar and electrostatic forces involved in drug/membrane interactions were quantified both as ΔlogkWIAM and as Δ′logkWIAM. These values are the differences between the experimental logkWIAM and the values expected for a neutral compound having the lipophilicity value equal to either that of the neutral form of the analyte (logPN) or that of the mixture of charged and neutral forms of the analyte at jejunum pH 6.5 (logD6.5), respectively. Jejunum absorption values, logPeff, measured by the Loc-I-Gut technique, did not relate with logkWIAM values. A moderate linear relationship was observed with logPN values for all the analytes and a weak parabolic relationship was observed with logD6.5 values, but only after the exclusion of two analytes. In contrast, a highly significant linear inverse relationship was observed with ΔlogkWIAM values. Therefore, differently from the results of our recent studies on blood–brain barrier passage, the intestinal absorption data for not only bases and zwitterions but also for acids relate significantly with ΔlogkWIAM and not with Δ′logkWIAM values.The results suggest that membrane passage at jejunum level can be described according to the “flip-flop” model; indeed, the lipophilicity of the neutral forms (logPN) appears related to the passage through the non-polar inner moieties of phospholipids whereas ΔlogkWIAM parameter appears related to the “trapping” forces at their polar surfaces.The method, easy to perform and at medium throughput, could be of use for preliminary screening of new drugs based on oral absorption potential.