Retention data of bile acids and their oxo derivatives in characterization of pharmacokinetic properties and in silico ADME modeling Jovana Trifunović a, ⁎, Vladan Borčić a , Saša Vukmirović a , Svetlana Goločorbin Kon b , Momir Mikov a a Department of Pharmacology, Toxicology and Clinical Pharmacology, Medical Faculty, University of Novi Sad, Hajduk Veljkova 3, 21000 Novi Sad, Serbia b Department of Pharmacy, Medical Faculty, University of Novi Sad, Hajduk Veljkova 3, 21000 Novi Sad, Serbia abstract article info Article history: Received 10 February 2016 Received in revised form 11 July 2016 Accepted 12 July 2016 Available online 14 July 2016 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 pur- pose 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 deter- mined hydrophobicity parameters and calculated logP values. Methods: Commercially available bile acids - deoxycholic, chenodeoxycholic, hyodeoxycholic and ursodeoxycholic acid were used to synthesize oxo derivatives. Lipophilicity was evaluated in two solvent sys- tems: toluene/ethanol and toluene/butanol. Retention parameters were acquired by normal-phase TLC. The cor- relations between calculated logP 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 ex- amined 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 pharmacoki- netic 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). © 2016 Elsevier B.V. All rights reserved. Keywords: Bile acids Oxo derivatives of bile acids ADME In silico correlation Multiple linear regression 1. Introduction Bile acids are amphiphilic compounds, composed of a steroid struc- ture with four rings, and they represent surface active substances (Calabresi et al., 2012). Surface activity of bile acids is enabled due to dif- ferences between two sides of the basic steroid ring α-side, which is perceived as concave side and β-side, which is defined as convex side (Armstrong and Carey, 1982). Bile acids synthesis is one of the most im- portant routes of cholesterol metabolism in mammals. Two pathways are significant in the synthesis of bile acids: classical and acidic pathway. Both of these pathways contribute in forming of primary bile acids, cholic acid (CA) and chenodeoxycholic (CDCA). Primary bile acids fur- ther undergo modifications of their chemical structure via conjugation with amino acids which leads to increasing hydrophobicity of the mol- ecule. After secretion into the lumen of intestine, conjugated bile acids become exposed to bacterial degradation and removal of glycine and taurine part, which allows production of secondary bile acids, deoxycholic acid (DCA) and lithocholic acid (LCA). All of synthesized bile acids can be returned to liver and re-secreted via enterohepatic cir- culation (Chiang, 2009; Heusser and Wurthier, 1947; Hirofuji, 1965). European Journal of Pharmaceutical Sciences 92 (2016) 194–202 Abbreviation: logP, logarithm of partition coefficient; R M 0 , intercept; b, slope of the linear plot; C, volume fraction of the organic solvent in the mobile phase; TPSA, total polar surface area; natoms, number of atoms; M w , molecular weight; nOH, number of hydrogen bond donors; nOHNH, number of hydrogen bond acceptors; nviol, number of violations; nrotb, number of rotatable bonds; V, molecular volume; logBB, logarithm of the blood-brain barrier partition coefficient; HIA, human intestinal absorption in percent; MDCK, in vitro Mandin Darby Canine Kidney cell permeability; PPB, plasma protein bound in percent; PE, jejunum pH = 6, 5 (cm/s); V d , human volume of distribution (l/kg); SP, skin permeability; GPCR, G-protein coupled receptor ligand; ICM, Ion channel modulator; NRL, Nuclear receptor inhibitor; PI, protease inhibitor. ⁎ Corresponding author. E-mail addresses: jovanatrifunovic@gmx.com, jovanatrifunovic@uns.ac.rs (J. Trifunović). http://dx.doi.org/10.1016/j.ejps.2016.07.011 0928-0987/© 2016 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect European Journal of Pharmaceutical Sciences journal homepage: www.elsevier.com/locate/ejps