title: Cytisine basicity, solvation, logP, and logD theoretical determination as tool for bioavailability prediction.
abstract: Cytisine, an α4β2 nicotinic receptor partial agonist, is a plant alkaloid widely used as a smoking cessation agent. Despite long history of use, knowledge on pharmacokinetics of cytisine still demands an extension. This work is aimed at theoretical determination of physicochemical parameters that affect the bioavailability of cytisine. The acidic dissociation constant, Gibbs free energy of solvation in water and n-octanol as well as n-octanol/water partition coefficient and n-octanol/water distribution coefficient of cytisine were calculated as quantities corresponding to its solubility and permeability. Cytisine structure was optimized with several quantum chemical methods-ab initio: HF and MP2, and DFT functionals (B3LYP, B3LYP-D3, CAM-B3LYP, M06-2X, TPSS, VSXC) with 6-311++G(d,p) basis set. Solvation of cytisine in water and n-octanol was determined with the SMD continuum model. It was shown that lipophilicity of cytisine depends on the pH of an environment. Protonated cytisine, the most populated state under acidic conditions, is characterized by enhanced hydrophilicity. Then neutral cytisine, dominating in a basic environment, demonstrates more lipophilic character. It appears that cytisine is very well soluble in the gastrointestinal (GI) tract fluids. Then the distribution of cytisine ought to occur very rapidly. However, permeability of cytisine through the mucous membrane of the GI tract may be limited, leading to the diminished bioavailability.
authors.affiliation: Department of Drug Chemistry, Faculty of Pharmacy with the Laboratory Medicine Division, Medical University of Warsaw, Banacha 1 Street, 02-097 Warsaw, Poland; Biomolecular Machines Laboratory, Centre of New Technologies of University of Warsaw, Banacha 2c Street, 02-097 Warsaw, Poland. Electronic address: tom.pienko@gmail.com.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Pieńko
authors.affiliation: Department of Drug Chemistry, Faculty of Pharmacy with the Laboratory Medicine Division, Medical University of Warsaw, Banacha 1 Street, 02-097 Warsaw, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Grudzień
authors.affiliation: Department of Drug Chemistry, Faculty of Pharmacy with the Laboratory Medicine Division, Medical University of Warsaw, Banacha 1 Street, 02-097 Warsaw, Poland.
authors.forename: Przemysław Paweł
authors.initials: PP
authors.lastname: Taciak
authors.affiliation: Department of Drug Chemistry, Faculty of Pharmacy with the Laboratory Medicine Division, Medical University of Warsaw, Banacha 1 Street, 02-097 Warsaw, Poland; National Medicines Institute, 30/34Chełmska Street, 00-725 Warsaw, Poland.
authors.forename: Aleksander Paweł
authors.initials: AP
authors.lastname: Mazurek
mesh_terms: D000470:Alkaloids / Q000737:chemistry*; D001392:Azocines / Q000737:chemistry; D001682:Biological Availability; D006801:Humans; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D008956:Models, Chemical; D008958:Models, Molecular; D009092:Mucous Membrane / Q000378:metabolism; D009538:Nicotine / Q000037:antagonists & inhibitors; D010539:Permeability; D011522:Protons; D011807:Quinolizines / Q000737:chemistry; D012995:Solubility; D012996:Solutions; D013816:Thermodynamics; D061485:Tobacco Use Cessation Devices; D000093843:Quinolizidine Alkaloids
chemical_list: D000470:Alkaloids; D001392:Azocines; D009538:Nicotine; D011522:Protons; D011807:Quinolizines; D012996:Solutions; C004712:cytisine; D000093843:Quinolizidine Alkaloids
keywords: Acidic dissociation constant (pK(a)); Distribution coefficient (logD); Gibbs free energy of solvation; Partition coefficient (logP)