On the observed large interspecies overprediction of human clearance ("vertical allometry") of UCN-01: further support for a proposed model based on plasma protein binding.
The prediction of a human clearance (CL) value for UCN-01, an extreme example of vertical allometry (a large overprediction by allometric scaling), was examined using commonly used simple allometry and the "rule of exponents," as well as a newly proposed model, which quantitatively incorporates plasma protein-binding information from rats and humans. Simple allometry and the rule of exponents were shown to overpredict the human CL value of UCN-01 by about 5000- and 1750-fold, respectively. The new model incorporating the ratio of fraction unbound between rats and humans improved the prediction by about 20-fold compared to the rule of exponents. The model is expected to improve if a more accurate measurement of the unbound fraction in human plasma is obtained. The prediction of volume distribution for UCN-01 by allometric scaling was also shown to be dependent on the difference of fraction unbound between animal species and humans. In summary, plasma protein binding has been demonstrated to be an important measure for interspecies scaling of pharmacokinetics.
Bioanalytical Department, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, USA. tangh3@wyeth.com
Huadong
H
Tang
Michael
M
Mayersohn
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism*; D006801:Humans; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D013045:Species Specificity; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics
D001798:Blood Proteins; D047428:Protein Kinase Inhibitors; C054852:7-hydroxystaurosporine; D019311:Staurosporine