Influence of molecular properties on oral bioavailability of lipophilic drugs – Mapping of bulkiness and different measures of polarity

Abstract

The biopharmaceutical assessment of new drug candidates based on their chemical structure is important in drug discovery and development. The scope of this study is to focus on lipophilic drugs and to clarify the role of their chemical predictors on oral bioavailability in humans. First their chemical properties were calculated from molecular modeling and the bioavailability data was obtained from the literature. The data was then analyzed by a partial least square method including non-linear terms. Significant coefficients were identified from a group of polarity- and solubility-related properties. Contour plots were constructed mapping molecular weight together with different polarity factors. Depending on the molecular weight a maximal bioavailability was found at solubility parameters of about 31–35 (J/cm3)1/2 and HLB values of roughly 4–12. The mapping of lipophilic drugs also revealed that a solubility parameter of less than 20 (J/cm3)1/2 or a HLB of smaller than unity is critical for the drug-likeness of new compounds.