Sabeluzole

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.

The in vitro-to-in vivo extrapolation (IVIVE) methods for predicting the hepatic clearance (CL) of drugs based on microsomal or hepatocyte data have certainly advanced; however, there is still place for improving the extrapolations from in vitro assays containing no plasma proteins. Accordingly, there is a discussion on whether the free drug hypothesis or an albumin (ALB)-mediated hepatic uptake phenomenon is the best scaling method. Therefore, the objectives of this study were to guide the prediction of CL and to diagnose which scaling method between the free drug hypothesis and ALB-mediated uptake could be more accurate; this, irrespective of the mechanism(s) governing CL if the drugs can get to the hepatocyte membrane. The analysis of several datasets demonstrated that almost all values of CL in vivo fall within the two calculated values of CL use as boundaries from: 1) the free drug hypothesis, and 2) ALB-mediated uptake. The average value from these two CL boundaries predicted the CL in vivo with an incredible accuracy. Validating these boundaries in preclinical species prior going to human as well as considering the fractional binding in plasma increased the accuracy. Overall, this study is another step towards guiding the CL prediction in drug discovery and development.