Document Detail


Interspecies scaling of clearance and volume of distribution data for five therapeutic proteins.
MedLine Citation:
PMID:  1798669     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The clearance and volume of distribution of five human proteins (recombinant CD4, CD4 immunoglobulin G, growth hormone, tissue-plasminogen activator, and relaxin) in humans and laboratory animals were analyzed as a function of body weight using allometric scaling techniques. These proteins cover a 16-fold range of molecular weight (6 to 98 kD), are produced by recombinant or synthetic methods, and may be cleared by different mechanisms. The analyses revealed that the clearance and volume data for each protein were satisfactorily described by an allometric equation (Y = a Wb). The allometric exponent (b) for clearance (ml/min) ranged from 0.65 to 0.84, the allometric exponent for the initial volume of distribution (ml) ranged from 0.83 to 1.05, and the allometric exponent for the volume of distribution at steady state (ml) ranged from 0.84 to 1.02. Exponent values from 0.6 to 0.8 for clearance and 0.8 to 1.0 for volumes are frequently cited for small molecules and are expected based on empirical interspecies relationships. When the preclinical data were analyzed separately, the preclinical allometric relationships were usually predictive of the human results. These findings indicate that the clearance and volume of distribution of select biomacromolecules follow well-defined, size-related physiologic relationships, and preclinical pharmacokinetic studies provide reasonable estimates of human disposition. Employing this methodology during the early phases of drug development may provide a more rational basis for dose selection in the clinical environment.
Authors:
J Mordenti; S A Chen; J A Moore; B L Ferraiolo; J D Green
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Publication Detail:
Type:  Comparative Study; Journal Article    
Journal Detail:
Title:  Pharmaceutical research     Volume:  8     ISSN:  0724-8741     ISO Abbreviation:  Pharm. Res.     Publication Date:  1991 Nov 
Date Detail:
Created Date:  1992-04-15     Completed Date:  1992-04-15     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  8406521     Medline TA:  Pharm Res     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1351-9     Citation Subset:  IM    
Affiliation:
Department of Pharmacokinetics, Genentech, Inc., South San Francisco, California 94080.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antigens, CD4 / metabolism
Growth Hormone / pharmacokinetics
Humans
Immunoglobulin G / metabolism
Macaca fascicularis
Macaca mulatta
Mice
Proteins / administration & dosage,  pharmacokinetics*
Rabbits
Rats
Recombinant Proteins / pharmacokinetics
Relaxin / pharmacokinetics
Species Specificity
Tissue Plasminogen Activator / pharmacokinetics
Chemical
Reg. No./Substance:
0/Antigens, CD4; 0/Immunoglobulin G; 0/Proteins; 0/Recombinant Proteins; 9002-69-1/Relaxin; 9002-72-6/Growth Hormone; EC 3.4.21.68/Tissue Plasminogen Activator

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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