Prediction of volume of distribution in preclinical species and humans: application of simplified physiologically based algorithms

The present study was aimed at developing simplified physiologically based semi-mechanistic algorithms to predict V _ss and interspecies scaling factors to predict tissue-K _p s which require minimum input parameters, diminish the computing complexity and have better predictability. V _ss of 86 structurally diverse compounds in preclinical species and 27 compounds in humans were predicted using only lung- and muscle-K _p as inputs. Interspecies scaling factor (s) were developed based on fold-differences in individual tissue lipid contents, relative organ blood flow: relative organ weight ratio between two species. Tissue-K _p s were predicted for 34 compounds using the newly developed interspecies scaling factors. The predicted-to-experimental V _ss values for all the 113 compounds was 1.3 ± 0.9 with 83% values being within a factor of two. The tissue-K _p s in rat, dog and human were predicted using experimental tissue-K _p data in rodents and interspecies scaling factors and here also, 83% of tissue-K _p s were within two-fold of the experimental values. In conclusion, simplified physiologically based algorithms have been developed to predict both volume of distribution and tissue-K _p s, in which required input parameters as well as computing complexity have been noticeably reduced.