Retention data of bile acids and their oxo derivatives in characterization of pharmacokinetic properties and in silico ADME modeling

Purpose Information on ADME properties of examined bile acids and their oxo derivatives are scarce, although the interest for bile acids and their use in nanochemistry and macromolecular chemistry is increasing. The purpose of this research was to evaluate the lipophilicity, a crucial physicochemical parameter for describing ADME properties of selected bile acids and their oxo derivatives, and to compare two approaches: experimentally determined hydrophobicity parameters and calculated log P values. Methods Commercially available bile acids - deoxycholic, chenodeoxycholic, hyodeoxycholic and ursodeoxycholic acid were used to synthesize oxo derivatives. Lipophilicity was evaluated in two solvent systems: toluene/ethanol and toluene/butanol. Retention parameters were acquired by normal-phase TLC. The correlations between calculated log P values obtained using five different software and experimentally determined hydrophobicity parameters ( R M 0 (tol/eth) , R M 0 (tol/but) , b (tol/eth) and b (tol/but) ) were examined. Results Correlation analysis confirmed significant dependence between experimental R M 0 values and software calculated parameters. Results suggest satisfactory intestinal absorption after oral administration for all of the examined compounds as well as low volumes of distribution, and high affinity for binding with plasma proteins. Penetration through blood-brain barrier and skin is not satisfactory. All of the examined compounds show high affinity for binding with G-protein coupled receptors and consequently inhibition of ionic channels. Results also suggest possible binding with nuclear receptors. Conclusions Established lipophilicity testing model of studied compounds showed excellent predictive ability and might represent significant tool in development of relations between chromatographic behavior and ADME properties. Compounds 3α-hydroxy-7,12-dioxo-5β-cholanoic and 12α-hydroxy-3,7-dioxo-5β-cholanoic acid might be the most suitable candidates for further development studies (satisfactory pharmacokinetic properties and lowest haemolytic potential) followed by 3α-hydroxy-12-oxo-5β-cholanoic acid and 3α-hydroxy-7-oxo-5β-cholanoic acid (slightly higher haemolytic potential, but better ligand properties).