Hiroshima International University, Faculty of Pharmaceutical Sciences, Laboratory of Biopharmaceutics and Pharmacokinetics, 5-1-1 Hiro-koshingai Kure Hiroshima, Kure 737-0112, Japan.
Expert Opin Drug Metab Toxicol. 2011 Mar;7(3):353-64. doi: 10.1517/17425255.2011.548805.
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.
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.
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.
具有至少一个官能团的 pK(a) 值≥7 的含胺碱性化合物或中等强度的胺，通常表现出较大的分布容积，且各组织之间存在明显差异。了解各种碱性化合物的组织分布机制对于药物设计很重要。
本综述重点介绍了组织磷酰丝氨酸（PS）结合在含胺碱性化合物特征性组织分布中的作用。阐明了组织分布的机制，包括细胞间和细胞内分布，以及 pK(a) 值和脂溶性对各种碱性化合物组织分布程度的影响。
膜通透性中等强度胺的组织分布程度取决于组织 PS 浓度和与 PS 的结合亲和力。每种化合物的组织分布程度与各种组织中的组织 PS 浓度之间存在线性关系。相比之下，pK(a) 值<6.5 的非常弱碱性化合物以几乎相当的程度分布到各种组织中，与组织 PS 浓度无关。了解组织分布机制并预测每种组织的 Kp 值对于控制各种含胺碱性化合物的药物治疗中的药理学和/或毒性作用以及药物设计至关重要。
