Interrogating the relationship between rat in vivo tissue distribution and drug property data for >200 structurally unrelated molecules

Abstract

The ability to explain distribution patterns from drug physicochemical properties and binding characteristics has been explored for more than 200 compounds by interrogating data from quantitative whole body autoradiography studies (QWBA). These in vivo outcomes have been compared to in silico and in vitro drug property data to determine the most influential properties governing drug distribution. Consistent with current knowledge, in vivo distribution was most influenced by ionization state and lipophilicity which in turn affected phospholipid and plasma protein binding. Basic and neutral molecules were generally better distributed than acidic counterparts demonstrating weaker plasma protein and stronger phospholipid binding. The influence of phospholipid binding was particularly evident in tissues with high phospholipid content like spleen and lung. Conversely, poorer distribution of acidic drugs was associated with stronger plasma protein and weaker phospholipid binding. The distribution of a proportion of acidic drugs was enhanced, however, in tissues known to express anionic uptake transporters such as the liver and kidney. Greatest distribution was observed into melanin containing tissues of the eye, most likely due to melanin binding. Basic molecules were consistently better distributed into parts of the eye and skin containing melanin than those without. The data, therefore, suggest that drug binding to macromolecules strongly influences the distribution of total drug for a large proportion of molecules in most tissues. Reducing lipophilicity, a strategy often used in discovery to optimize pharmacokinetic properties such as absorption and clearance, also decreased the influence of nonspecific binding on drug distribution.

Improving Nonspecific Binding and Solubility: Bicycloalkyl Groups and Cubanes as para‐Phenyl Bioisosteres

“…Nonspecific binding (NSB) strongly influences the quality of imaging agents, as well as the pharmacological properties of drug candidates . The identification of such molecules often requires extensive optimization efforts.…”

“…Nonspecific binding (NSB) strongly influences the quality of imaging agents, [1,2] as well as the pharmacological properties of drug candidates. [3] The identification of such molecules often requires extensive optimization efforts. After am edicinal chemistry program hasadvanced beyond acertain stage, it becomes very challenging to significantly improvet he physicochemicalp roperties of advanced candidates without losing desirable pharmacological properties.…”

In vitro and in vivo evidence of tyrosinase inhibitory activity of a synthesized (Z)‐5‐(3‐hydroxy‐4‐methoxybenzylidene)‐2‐thioxothiazolidin‐4‐one (5‐HMT)

“…This may be due to improvement in lipophilicity (log P) of 5‐HMT by substitution of sulphur atoms (Figures , ). It was reported that lipophilicity of a small molecule will influence membrane partitioning and cell permeability . Furthermore, Fontana‐Masson staining was used to spot melanocytes in the epidermis of the UV‐exposed dorsal skin and confirmed that melanocyte spots were decreased in 5‐HMT‐treated mice (Figure C).…”

“…It was reported that lipophilicity of a small molecule will influence membrane partitioning and cell permeability. [10] Furthermore, Fontana-Masson staining was used to spot melanocytes in the epidermis of the UV-exposed dorsal skin and confirmed that melanocyte spots were decreased in 5-HMT-treated mice ( Figure 2C). As a confirmatory measure of UV-induced melanogenesis and depigmentation effects of 5-HMT, immunohistochemistry staining using S100 protein, widely-used melanocyte marker protein, was performed.…”

C−H Functionalization—Prediction of Selectivity in Iridium(I)‐Catalyzed Hydrogen Isotope Exchange Competition Reactions

“…The HIE reaction has become a broadly utilized and elegant method for the incorporation of deuterium or tritium into organic molecules, circumventing the need for a tedious multi-step synthesis. [2] In drug discovery, radioactive tritium substances are used as research tools [3,4] for example, for understanding tissue distribution, [5] in covalent binding assays, [6] or for ADME (absorption distribution metabolism excretion) profiling of new drug candidates. [7] Numerous HIE protocols utilizing homogeneous or heterogeneous catalysts have already been described.…”