Phospholipid affinity indexes (log 𝑘 ᴵᴬᴹ/W) 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 ∆ log 𝑘 ᴵᴬᴹ/W and as ∆'log 𝑘 ᴵᴬᴹ/W . These values are the differences between the experimental log 𝑘 ᴵᴬᴹ/W and the values expected for a neutral compound having the lipophilicity value equal to either that of the neutral form of the analyte (log Pᴺ) or that of the mixture of charged and neutral forms of the analyte at jejunum pH 6.5 (log D⁶.⁵), respectively. Jejunum absorption values, log Peff, measured by the Loc-I-Gut technique, did not relate with log 𝑘 ᴵᴬᴹ/W values. A moderate linear relationship was observed with log Pᴺ values for all the analytes and a weak parabolic relationship was observed with log D⁶.⁵ values, but only after the exclusion of two analytes. In contrast, a highly significant linear inverse relationship was observed with log 𝑘 ᴵᴬᴹ/W 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 ∆log 𝑘 ᴵᴬᴹ/W and not with ∆'log 𝑘 ᴵᴬᴹ/W 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 (log PN) appears related to the passage through the non-polar inner moieties of phospholipids whereas 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.