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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
Author(s) -
Tang Huadong,
Mayersohn Michael
Publication year - 2006
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270005285457
Subject(s) - allometry , scaling , biological system , chemistry , fraction (chemistry) , mathematics , biology , chromatography , ecology , geometry
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.