Drug discovery pharmacokinetic model

Theil FP, Guentert TW, Haddad S, Poulin P. Utility of physiologically based pharmacokinetic models to drug development and rational drug discovery candidate selection. Toxicol Lett 2003 Feb 18 138(l-2) 29-49. Review. 

Parrott, N Paquereau, N Coassolo, P Lave, Th. An evaluation of the utility of physiologically based models of pharmacokinetics in early drug discovery. f Pharm. Sci. 2005, 94, 2327-2343. 

Physiologically based pharmacokinetic models provide a format to analyze relationships between model parameters and physicochemical properties for a series of drug analogues. Quantitative structure-pharmacokinetic relationships based on PB-PK model parameters have been pursued [12,13] and may ultimately prove useful in the drug development process. In this venue, such relationships, through predictions of tissue distribution, could expedite drug design and discovery. 

In spite of its limitations, the ACAT model combined with modeling of saturable processes has become a powerful tool in the study of oral absorption and pharmacokinetics. To our knowledge, it is the only tool that can translate in vitro data from early drug discovery experiments all the way to plasma concentration profiles and nonlinear dose-relationship predictions. As more experimental data become available, we believe that the model will become more comprehensive and its predictive capabilities will be further enhanced. 

Sinko, P. J., Grass, G. M., Development of predictive pharmacokinetic simulation models for drug discovery, /. Controlled Release 2000, 65, 55—62. 

From the above we conclude that in silico absorption models are very useful tools in assessing the development potential of compounds in the drug discovery process, and their use in discovery projects could help to reduce the attrition rate due to poor pharmacokinetic properties in later phases. The... 

QSAR and neural network approaches in combination with physiologicaUy-based pharmacokinetic (PBPK) modelling hold promise in becoming a powerful tool in drug discovery [45]. Below we briefly discuss some of these studies. 

Having access to metabolism data in the early discovery stage is invaluable. For example, hepatic metabolism data could be used to characterize the pharmacokinetic behavior of a perspective lead. Several studies have reported how metabolism databases and software systems have been used at various settings (272). In this section, we will provide an overview of recent databases, software systems, websites, tools, and services that could be potential starting points for metabolism modeling at various stages in drug discovery process (271,273). 

Membrane permeability is one of the most important determinants of pharmacokinetics, not only for oral absorption, but also for renal re-absorption, biliary excretion, skin permeation, distribution to a specific organ and so on. In addition, modification of membrane permeability by formulation is rarely successful. Therefore, membrane permeability should be optimized during the structure optimization process in drug discovery. In this chapter, we give an overview of the physiology and chemistry of the membranes, in vitro permeability models and in silica predictions. This chapter focuses on progress in recent years in intestinal and blood-brain barrier (BBB) membrane permeation. There are a number of useful reviews summarizing earlier work [1-5]. 

In a recent review of pharmacokinetics in drug discovery, Ruiz-Garcia et al. [81] compiled an exhaustive list of software resources for absorption prediction. The main topic in the described databases is transporters, in particular the ATP-binding cassette, of which the efflux transporter P-gp and the peptide transporter PEPTl are well known examples. These examples show that science is moving away from the simplistic passive transport view of permeability and towards an all-inclusive, mechanism-understanding model of absorption, which takes account of all the interactions between the agents involved in the specific permeation process. 

Poulin, P. and Theil, E.P. (2000) A priori prediction of tissue plasma partition coefficients of drugs to facilitate the use of physiologically-based pharmacokinetic models in drug discovery. Journal of Pharmaceutical Sciences, 89, 16-35. 

As occurred with the introduction of in vitro testing for adverse pharmacokinetic properties, implementation of in vitro cytotoxicity testing in drug discovery is likely to reduce later attrition in drug development by an order of magnitude. An indispensable tool will be HCA and a cytotoxicity model similar to that described above. Attendance at the numerous annual industry conferences on HCA indicates that... 

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