Physiologically based modeling of p-tert-octylphenol kinetics following intravenous, oral or subcutaneous exposure in male and female Sprague-Dawley rats.
J Appl Toxicol
; 30(5): 437-49, 2010 Jul.
Article
in En
| MEDLINE
| ID: mdl-20186885
ABSTRACT
The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model for p-tert-octylphenol (OP) for understanding the qualitative and quantitative determinants of its kinetics in Sprague-Dawley rats. Compartments of the PBPK model included the liver, richly perfused tissues, poorly perfused tissues, reproductive tissues, adipose tissue and subcutaneous space, in which OP uptake was described as a blood flow- or a membrane diffusion-limited process. The PBPK model successfully simulated previously published data on blood and tissue OP concentrations in Sprague-Dawley rats following oral, intravenous (i.v.) or subcutaneous (s.c.) routes. The model predicted that OP concentrations would reach 6.8, 13.8 and 27.9 ng ml(-1) (male) and 7.2, 14.7 and 31.4 ng ml(-1) (female), 4 h after a single i.v. dose of 2, 4 and 8 mg kg(-1), respectively. The model also predicted that OP concentrations would reach 53.3, 134.8 and 271.2 ng ml(-1) (male) and 87.4, 221.4 and 449.7 ng ml(-1) (female) 4 h after a single oral dose (50, 125 and 250 mg kg(-1)) and that, 4 h after a single s.c. dose (125 mg kg(-1)), OP concentrations would reach 111.3 ng ml(-1) (male) and 121.6 ng ml(-1). A marked sex difference was seen in blood and tissue OP concentrations. This was reflected in the model by a gender-specific maximal velocity of metabolism (V(max)) that was higher (1.77 x) in male than in female rats. Further studies are required to elucidate the mechanism underlying the gender differences and to evaluate whether that is also observed in humans.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Phenols
/
Surface-Active Agents
Type of study:
Prognostic_studies
/
Qualitative_research
Limits:
Animals
Language:
En
Journal:
J Appl Toxicol
Year:
2010
Document type:
Article
Affiliation country:
Canadá