Polar interactions drug/phospholipids estimated by IAM-HPLC vs cultured cell line passage data: Their relationships and comparison of their effectiveness in predicting drug human intestinal absorption

The relationships between data of passage through Caco-2 cultured cell lines (log Papp), taken from the literature, for 38 structurally unrelated compounds and both n-octanol lipophilicity parameters (log P(N) and log D(7.4)) and phospholipid affinity indexes were investigated. Phospholipid affinity(log k W(IAM)) was experimentally determined by HPLC on two different phospholipid stationary phases and the polar/electrostatic interaction component drug/phospholipids (Δ log k W(IAM)) was calculated according to a method we previously proposed. Log Papp moderately related to lipophilicity values measured at pH 7.4 (log D(7.4)), according to a parabolic pattern, but poorly related with log k W(IAM). Furthermore, a significant inverse linear relationship with Δ l og k W(IAM) values was only observed for the analytes with m.w. >300 Da, for which paracellular diffusion can be considered a minor transport route in vivo. Indeed, it has been reported that Caco-2 passage data also encode secondary passage mechanisms, which participate in a different extent to the jejunal absorption in vivo and cannot be directly equated to the corresponding human in situ log Peff values, unless a normalization is performed. In an attempt to elucidate this issue, 47 structurally unrelated compounds whose cultured cell line passage data were corrected for the effects of the aqueous boundary layer and paracellular permeability, so as to express transcellular intrinsic permeability, log P 0(Caco-2/MDCK), were also considered. Highly significant inverse linear relationships were observed between log P 0(Caco-2/MDCK) and Δlog k W(IAM) values from both IAM.PC.MG (r(2)=0.765) and IAM.PC.DD2 (r(2)=0.806) stationary phases whereas the relationships with either lipophilicity in n-octanol or log k W(IAM) values were very poor. The results of the present study, in complete agreement with those of our recent study on the relationships between jejunal absorption data measured in situ and Δ log k W(IAM) values, confirm the soundness of Δ log k W(IAM) parameters in the prediction of the intestinal absorption of drugs. From a mechanistic point of view, they suggest that the polar/electrostatic forces between drugs and phospholipids play a major role in the passage through biomembranes.