Interspecies scaling: Role of protein binding in the prediction of clearance from animals to humans

The objective of this study is to evaluate whether unbound clearance of a d rug can be predicted more accurately than total clearance using the allomet ric approach and if there is any real advantage of predicting unbound clear ance over total clearance. The total and unbound clearance of 20 randomly s elected drugs were scaled up from the animal data (at least three animal sp ecies) obtained from the literature. Three methods were used to generate pl ots to scale up the clearance values: (I) total or unbound clearance versus body weight (simple allometric equation), (2) the product of total or unbo und clearance and maximum life span potential (MLP) versus body weight, and (3) the product of total or unbound clearance and brain weight versus body weight. The results of this study indicate that there will be instances wh en unbound clearance can be predicted better than total clearance or vice v ersa. In conclusion, unbound clearance cannot be predicted any better than total clearance. (C)2000 the American College of Clinical Pharmacology.