Edinburgh Napier University

  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 Pᴺ and log D⁷.⁴) and phospholipid affinity indexes were investigated. Phospholipid affinity (log 𝑘 ᴵᴬᴹ/W) was experimentally determined by HPLC on two different phospholipid stationary phases and the polar/electrostatic interaction component drug/phospholipids (∆log 𝑘 ᴵᴬᴹ/W) was calculated according to a method we previously proposed. Log Pₐₚₚ moderately related to lipophilicity values measured at pH 7.4 (log D⁷.⁴), according to a parabolic pattern, but poorly related with log 𝑘 ᴵᴬᴹ/W. Furthermore, a significant inverse linear relationship with ∆log 𝑘 ᴵᴬᴹ/W 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 Pₑբբ 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 P₀ᶜᵃᶜᵒ⁻²/ᴹᴰᶜᴷ, were also considered. Highly significant inverse linear relationships were observed between log P₀ᶜᵃᶜᵒ⁻²/ᴹᴰᶜᴷ and ∆log 𝑘 ᴵᴬᴹ/W values from both IAM.PC.MG (r2 = 0.765) and IAM.PC.DD2 (r2 = 0.806) stationary phases whereas the relationships with either lipophilicity in n-octanol or log 𝑘 ᴵᴬᴹ/W 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 ∆log 𝑘 ᴵᴬᴹ/W values, confirm the soundness of ∆log 𝑘 ᴵᴬᴹ/W 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.