Animal species, i.e. rats, are used to evaluate a drugs biol. activity and pharmacokinetics, such as clearance.This study aims to develop a predictive method to evaluate the relationship between the clearance of drugs in rats and humans.Adataset of 395 drugs composed of human and rat clearance data was applied in this study.The drugs, according to the clearance differences, were divided into two groups on the basis of the correlation between humans and rats.Structural parameters were used to develop a model to estimate the class of each drug by binary logistic regression.The results showed that the developed models are a useful way to show which drug have an acceptable correlation between human and rat clearance by using structural features.They can be used to determine the group of drugs with an accuracy of 74%.According to the validation results, the developed method has an acceptable accuracy for checking the relationship between the clearance of drugs in humans and rats.This modeling can be used to exclude the drugs from experiments in rats which reveal a considerable difference between the clearance of humans and that of rats.

01 Dec 2014·Pharmaceutical researchQ3 · MEDICINE

Prediction of Drug Distribution in Rat and Humans Using an Artificial Neural Networks Ensemble and a PBPK Model

Q3 · MEDICINE

Article

Author: Natália Aniceto ; Paulo Paixão ; José A. G. Morais ; Luís F. Gouveia

PURPOSE:

To develop a QSAR model, based on calculated molecular descriptors and an Artificial Neural Networks Ensemble (ANNE), for the estimation of rat tissue-to-blood partition coefficients (Kt:b), as well as the assessment of the applicability domain of the model and its utility in predicting the drug distribution in humans.

METHODS:

A total of 1460 individual Kt:b values (75% train and 25% validation), obtained in 13 different rat tissues were collected in the literature. A correlation between simple molecular descriptors for lipophilicity, ionization, size and hydrogen bonding capacity and Kt:b data was attempted by using an ANNE.

RESULTS:

Similar statistics were observed between the train and validation group of data with correlations, between the observed values and the predicted average ANNE values, of 0.909 and 0.896, respectively. A degradation of the correlations was observed for predicted values with high uncertainty, as judged by the standard deviations of the ANNE outputs. This was further observed when using the ANNE Kt:b values in a Physiologically based pharmacokinetic (PBPK) model for predicting the Human Volume of distribution of another 532 drugs.

CONCLUSIONS:

This model (available as a MS Excel® workbook in the Supporting material of this article) may be a valuable tool for prediction and simulation in early drug development, allowing the in silico estimation of rat Kt:b values for PBPK purposes and also indicating its applicability domain.

01 Jul 2011·Drug metabolism and disposition: the biological fate of chemicalsQ2 · MEDICINE

Species Independence in Brain Tissue Binding Using Brain Homogenates

Q2 · MEDICINE

Article

Author: Liston, Theodore E. ; Troutman, Matthew D. ; Scott, Dennis O. ; Huang, Youping ; Di, Li ; Lin, Zhen ; Umland, John P. ; Chang, George

Species independence of brain tissue binding was assessed with a large number of structurally diverse compounds using equilibrium dialysis with brain homogenates of seven species and strains (Wistar Han rat, Sprague-Dawley rat, CD-1 mouse, Hartley guinea pig, beagle dog, cynomolgus monkey, and human). The results showed that the fractions unbound of the seven species and strains were strongly correlated with correlation coefficients ranging from 0.93 to 0.99. The cross-species/strain correlations were not significantly different from the interassay correlation with the same species. The linear correlation between Wistar Han and other species had a slope close to 1 and an intercept near 0. Based on orthogonal statistical analysis, no correction is needed for extrapolation of fraction unbound from Wistar Han rat to the other species or strains. Hence, brain tissue binding of Wistar Han rat can be used to obtain binding of other species and strains in drug discovery.

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Indication	Highest Phase	Country/Location	Organization	Date
Stroke	Phase 1	United Kingdom	Pfizer Inc.	02 Dec 2001

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