Role of phosphatidylserine binding in tissue distribution of amine-containing basic compounds.

INTRODUCTION: Amine-containing basic compounds with pK(a) values of ≥ 7 for at least one functional group, or moderately strong amines, typically exhibit large distribution volumes with a marked interorgan variation. Understanding the tissue distribution mechanisms of various basic compounds is important for drug design. AREAS COVERED: This review focuses on the role of tissue phosphatidylserine (PS) binding in the characteristic tissue distribution of amine-containing basic compounds. The mechanisms underlying tissue distribution, including intercellular and intracellular distribution, and effects of pK(a) values and lipophilicity on the extent of tissue distribution of various basic compounds are clarified. EXPERT OPINION: The extent of tissue distribution of membrane-permeable moderately strong amines depends on tissue PS concentrations and binding affinities to PS. A linear relationship is observed between the extent of tissue distribution of each compound and tissue PS concentrations in various tissues. In contrast, very weakly basic compounds with pK(a) values of < 6.5 distribute to various tissues at almost comparable magnitudes, independent of tissue PS concentrations. Understanding the tissue distribution mechanisms and predicting Kp values for each tissue is essential in controlling pharmacological and/or toxic effects in pharmacotherapy with various amine-containing basic compounds, as well as in drug design.