Prediction of hepatic metabolic clearance based on interspecies allometricscaling techniques and in vitro in vivo correlations

This article reviews the methods available for predicting hepatic metabolic clearance in humans, and discusses their application to the processes of d rug discovery and development, The application of these techniques has incr eased markedly during the past few years because of the improved availabili ty of human liver samples, which has increased the opportunities to use in vitro studies to predict human clearance, The techniques available involve both empirical and physiologically based approaches, Allometric scaling usi ng in vitro data from animals and humans combines certain aspects of both a pproaches, An evaluation of data retrieved from the literature indicates that, togethe r with in vitro human data, allometric scaling based on a combination of in vitro and in vivo preclinical data can accurately predict clearance in hum ans, With this approach, 80% of the predictions were within a 2-fold factor of actual human clearance values, with an overall accuracy of 1.6-fold. The uncertainties and inaccuracies in predicting human clearance are relate d to: (i) the specific method that is used to make the prediction: (ii) the experimental design and the model used to determine the in vitro clearance : (iii) protein binding within the in vitro test system; and (iv) various i n vivo factors such as the involvement of extrahepatic metabolism and activ e transport processes, interindividual variability and nonlinearity in phar macokinetics, In contrast to purely empirical approaches, the physiological approach to p redicting clearance fives an opportunity to integrate some of these complex ities and, therefore, should provide more confidence in the prediction of c learance in humans.