Prediction of Partition Coeffecients and Permeability of Drug Molecules in Biological Systems with Abraham Model Solute Descriptors Derived from Measured Solubilities and Water-to-Organic Solvent Partition Coefficients Page: 91
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Prediction of Partition Coefficients
and Permeability of Drug Molecules
in Biological Systems with Abraham Model
Solute Descriptors Derived from Measured
Solubilities and Water-to-Organic Solvent
William E. Acree, Jr.l, Laura M. GrubbsI and Michael H. Abraham2
'University of North Texas,
2University College London,
Modern drug testing and design includes experimental in vivo and in vitro measurements,
combined with in silico computations that enable prediction of the drug candidate's ADMET
(adsorption, distribution, metabolism, elimination and toxicity) properties in the early stages
of drug discovery. Recent estimates place the discovery and development cost of a small
drug molecule close to US $1.3 billion, from the time of inception to the time when the drug
finally reaches the market place. Only 20 % of conceived drug candidates proceed to clinical
trial stage testing, and of the compounds that enter clinical development less than 10 %
receive government approval. Reasons for the low success rate include unsatisfactory
efficacy, poor solubility, poor bioavailability, unfavorable pharmacokinetic properties,
toxicity concerns and drug-drug interactions, degradation and poor shelf-life stability.
Unfavorable pharmacokinetic and ADME properties, toxicity and adverse side effects
account for up to two-thirds of drug failures. Traditional ADME analyses relied heavily on
whole animal assays and the more labor intensive biochemical studies. High throughput
screening methods, fast ADMET profiling assays, and computational approaches have
allowed the pharmaceutical industry to identify quickly the less promising drug candidates
in the very early development stage so that time and valuable resources are not spent
pursuing compounds that have little probability of reaching the general population.
Of the fore-mentioned properties, the drug's aqueous solubility will likely be one of the first
properties measured. Aqueous solubility is a major indicator of the drug's solubility in
physiological gastrointestinal fluids and is a major indicator of the drug's oral
bioavailability. Approximately 40 % of the proposed new pharmaceutical candidates are
rejected in the very early stages of drug discovery because of their poor aqueous solubility
resulting in bioavailability problems (Lukyanov and Torchilin, 2004; Keck et al., 2008). The
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Acree, William E. (William Eugene); Grubbs, Laura M. & Abraham, M. H. (Michael H.). Prediction of Partition Coeffecients and Permeability of Drug Molecules in Biological Systems with Abraham Model Solute Descriptors Derived from Measured Solubilities and Water-to-Organic Solvent Partition Coefficients, chapter, February 10, 2012; [Rijeka, Croatia]. (digital.library.unt.edu/ark:/67531/metadc152436/m1/1/: accessed December 10, 2017), University of North Texas Libraries, Digital Library, digital.library.unt.edu; crediting UNT College of Arts and Sciences.