DMD Simcyp

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

0090-9556/05/3301-115-120$20.00
DMD 33:115-120, 2005

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Griffin, S. J.
Right arrow Articles by Houston, J. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Griffin, S. J.
Right arrow Articles by Houston, J. B.

PREDICTION OF IN VITRO INTRINSIC CLEARANCE FROM HEPATOCYTES: COMPARISON OF SUSPENSIONS AND MONOLAYER CULTURES

Sarah J. Griffin1, and J. Brian Houston

School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, United Kingdom

Due to the time-dependent loss of cytochrome P450 (P450)-mediated metabolism in freshly isolated hepatocytes, several types of culture systems have been developed to extend their lifespan. The aim of this study was to evaluate the ability of monolayer cultures of rat hepatocytes to determine the in vitro CLint compared with suspensions of freshly isolated hepatocytes. Seven compounds were incubated in rat hepatocyte suspensions and monolayer cultures, and in vitro CLint was obtained via metabolite formation (12 pathways) or substrate depletion approaches. Only two compounds (tolbutamide and 7-ethoxycoumarin) gave comparable (within 2-fold) in vitro CLint in both suspensions and monolayer cultures. Although the overall rank order of compounds was the same in both models (covering a range of 3-4 orders of magnitude), the prediction of in vitro CLint for high-turnover compounds (seven pathways) was lower for monolayer cultures compared with suspensions, probably due to an uptake rate limitation leading to increases in KM. In general, there was an average 50% loss of the P450 activity in monolayers based on a decrease in Vmax relative to suspensions. However, monolayer cultures gave a higher estimation of in vitro CLint for the low-turnover compound S-warfarin compared with fresh cell suspensions due to a decrease in the KM of the four individual metabolites. The use of hepatocyte monolayer cultures may offer the potential advantage of extending the lower end of the usable clearance range (below 0.1 µl/min/106 cells) for predicting in vivo CLint

Address correspondence to: Professor Brian Houston, School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester, M13 9PL, UK. E-mail: brian.houston{at}man.ac.uk




This article has been cited by other articles:


Home page
 Drug Metab. Dispos.Home page
J. J. Engtrakul, R. S. Foti, T. J. Strelevitz, and M. B. Fisher
ALTERED AZT (3'-AZIDO-3'-DEOXYTHYMIDINE) GLUCURONIDATION KINETICS IN LIVER MICROSOMES AS AN EXPLANATION FOR UNDERPREDICTION OF IN VIVO CLEARANCE: COMPARISON TO HEPATOCYTES AND EFFECT OF INCUBATION ENVIRONMENT
Drug Metab. Dispos., November 1, 2005; 33(11): 1621 - 1627.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2005 by the American Society for Pharmacology and Experimental Therapeutics.