title: Toward an integrated human clearance prediction strategy that minimizes animal use.
abstract: Prediction of human clearance plays a critical role in early drug discovery and development. However, there is no consensus on the most appropriate method to gather such data. A variety of in vivo and in vitro methods exist and a comparison of in vitro data from a standard set of compounds has been called for. This paper compares the predictive capacity of human liver microsomes and single-species scaling (SSS) from rat and non-human primate for a standard set of compounds representing marketed drugs. The results enable a framework to be proposed wherein compounds are selected using in vitro methods alone or in vitro methods combined with SSS in the rat. Further investigation of this framework has the potential to increase the efficiency of drug discovery and reduce animal use.
authors.affiliation: Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Sandwich Laboratories, Sandwich, Kent CT13 9NJ, UK. kevin.beaumont@pfizer.com.
authors.forename: Kevin
authors.initials: K
authors.lastname: Beaumont
authors.forename: Iain
authors.initials: I
authors.lastname: Gardner
authors.forename: Kathryn
authors.initials: K
authors.lastname: Chapman
authors.forename: Michael
authors.initials: M
authors.lastname: Hall
authors.forename: Malcolm
authors.initials: M
authors.lastname: Rowland
mesh_terms: D000826:Animal Testing Alternatives; D000818:Animals; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D065669:Hepatobiliary Elimination; D006801:Humans; D007527:Isoenzymes; D008862:Microsomes, Liver / Q000201:enzymology*; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011323:Primates; D051381:Rats; D065667:Renal Elimination; D015203:Reproducibility of Results; D013045:Species Specificity
chemical_list: D007527:Isoenzymes; D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System