Poulin, Patrick published the artcileApplication of the Tissue Composition-Based Model to Minipig for Predicting the Volume of Distribution at Steady State and Dermis-to-Plasma Partition Coefficients of Drugs Used in the Physiologically Based Pharmacokinetics Model in Dermatology, Computed Properties of 72509-76-3, the main research area is dermis partition drug pharmacokinetics model dermatol; IVIVE; PBPK modeling; discovery; in silico; pharmacokinetics; tissue composition; topical; transdermal.
The minipig continues to build a reputation as a viable alternative large animal model to predict humans in dermatol. and toxicol. studies. Therefore, it is essential to describe and predict the pharmacokinetics in that species to speed up the clin. candidate selection. Essential input parameters in whole-body physiol. based pharmacokinetic models are the tissue-to-plasma partition coefficients and the resulting volume of distribution at steady-state (Vss). Mechanistic in vitro- and in silico-based models used for predicting these parameters of tissue distribution of drugs refer to the tissue composition-based model (TCM). Robust TCMs were initially developed for some preclin. species (e.g., rat and dog) and human; however, there is currently no model available for the minipig. Therefore, the objective of this present study was to develop a TCM for the minipig and to estimate the corresponding tissue composition data. Drug partitioning into the tissues was predominantly governed by lipid and protein binding effects in addition to drug solubilization and pH gradient effects in the aqueous phase on both sides of the biol. membranes; however, some more complex tissue distribution processes such as drug binding to the collagen-laminin material in dermis and a restricted drug partitioning into membranes of tissues for compounds that are amphiphilic and contain sulfur atom(s) were also challenged. The model was validated by predicting Vss and the dermis-to-plasma partition coefficients (Kp-dermis) of 68 drugs. The prediction of Kp-dermis was extended to humans for comparison with the minipig. The results indicate that the extended TCM provided generally good agreements with observations in the minipig showing that it is also applicable to this preclin. species. In general, up to 86% and 100% of the predicted Vss values are resp. within 2-fold and 3-fold errors compared to the exptl. determined values, whereas these numbers are 78% and 94% for Kp-dermis when the anticipated outlier compounds are not included. Binding data to dermis are comparable between minipigs and humans. Overall, this study is a first step toward developing a mechanistic TCM for the minipig, with the aim of increasing the use of physiol. based pharmacokinetic models of drugs for that species in addition to rats, dogs, and humans because such models are used in preclin. and clin. transdermal studies.
Journal of Pharmaceutical Sciences (Philadelphia, PA, United States) published new progress about Blood plasma. 72509-76-3 belongs to class pyridine-derivatives, name is 3-Ethyl 5-methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C18H19Cl2NO4, Computed Properties of 72509-76-3.