Document Detail

Modeling the in vitro intrinsic clearance of the slowly metabolized compound tolbutamide determined in sandwich-cultured rat hepatocytes.
MedLine Citation:
PMID:  15258115     Owner:  NLM     Status:  MEDLINE    
An alternative approach is introduced in determining the in vitro intrinsic clearance of slowly metabolized compounds. The longterm sandwich rat hepatocyte culture was exploited, allowing for sufficient substrate depletion to obtain a reliable clearance estimation; in its physiology, it resembles the in vivo liver, thus allowing in vivo extrapolation of the in vitro clearance value. Substrate depletion of tolbutamide and the formation of its metabolites hydroxytolbutamide and carboxytolbutamide were measured in the medium and sandwich layer. Depletion data from the medium were fitted to a mathematical model incorporating system-dependent parameters (diffusion, protein binding, and partitioning) to calculate the hepatocytes' intrinsic clearance. Based on the decrease of the parent compound in the medium, a specific intrinsic clearance value, i.e., clearance per unit of volume of hepatocytes, of 0.085 min(-1) was fitted. This value was in accordance with in vivo and in vitro values from the literature. The model was verified with substrate depletion data from the sandwich layer. Data on metabolite formation showed an incomplete mass balance. A radiochemical experiment revealed the presence of three additional metabolites. These metabolites were analyzed by liquid chromatography-mass spectometry. One was identified as p-tolysulfonylurea. The structure of the other two needs to be elucidated. After the addition of these compounds to the metabolic pattern, the mass balance was completed. The in vitro clearance value was incorporated in a physiologically based pharmacokinetic literature model of tolbutamide that accurately describes the plasma concentration. The approach used in this study successfully predicts the intrinsic clearance of tolbutamide. In addition, the sandwich rat hepatocyte culture also proves to be useful in the identification of metabolic pathways.
Nicoline Treijtel; Arjan Barendregt; Andreas P Freidig; Bas J Blaauboer; Jan C H van Eijkeren
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  32     ISSN:  0090-9556     ISO Abbreviation:  Drug Metab. Dispos.     Publication Date:  2004 Aug 
Date Detail:
Created Date:  2004-07-19     Completed Date:  2005-01-18     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  United States    
Other Details:
Languages:  eng     Pagination:  884-91     Citation Subset:  IM    
Institute for Risk Assessment Sciences, Utrecht University, Yalelaan 2, P.O. Box 80176, 3508 TD Utrecht, The Netherlands.
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MeSH Terms
Cells, Cultured
Hepatocytes / metabolism*
Metabolic Clearance Rate / physiology
Models, Biological*
Rats, Wistar
Tolbutamide / chemistry,  metabolism*
Reg. No./Substance:

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