Cytisine basicity, solvation, log P, and log D theoretical determination as tool for bioavailability prediction

•Boltzmann populations of cytisine conformations in water were computed.•Theoretical pKa of cytisine is in accordance with experiment.•The Gibbs free energy of solvation of cytisine was calculated to rate solubility.•The log P and log D of cytisine were determined to predict permeability.•Cytisine should be categorized in the III class of BCS.

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.

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