DMD Noab BioDiscoveries - Shaping Drug Discovery

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


     

Drug Metabolism and Disposition Fast Forward
First published on June 10, 2005; DOI: 10.1124/dmd.105.005033

0090-9556/05/3309-1319-1324$20.00
DMD 33:1319-1324, 2005

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
dmd.105.005033v1
33/9/1319    most recent
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 Giuliano, C.
Right arrow Articles by Laufer, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Giuliano, C.
Right arrow Articles by Laufer, R.

DIRECT DETERMINATION OF UNBOUND INTRINSIC DRUG CLEARANCE IN THE MICROSOMAL STABILITY ASSAY

Claudio Giuliano, Mark Jairaj, Christian M. Zafiu, and Ralph Laufer

Department of Pharmacology, Istituto di Ricerche di Biologia Molecolare (IRBM) P. Angeletti, Merck Research Laboratories, Rome, Italy

The microsomal stability assay is commonly used to rank compounds according to their metabolic stability. Determination of the unbound intrinsic clearance (CLin,u) is essential for the accurate comparison of compounds, since nonspecific binding to microsomes can lead to an underestimation of the microsomal clearance. In this study, a new method (linear extrapolation in the stability assay, LESA) was established, which allows direct calculation of CLin,u from microsomal stability data, without the need to independently determine the fraction of free (unbound) drug. The method was validated using nine drugs with different chemical structures and physicochemical properties. The CLin,u of these compounds was extrapolated from the intrinsic clearance values obtained at different concentrations of human liver microsomes and compared with that calculated by the conventional method, using microsomal intrinsic clearance values and the free fraction of drug determined by equilibrium dialysis, ultracentrifugation, or ultrafiltration. A good agreement was observed between the data generated by the LESA method and those determined by conventional procedures. The method was further evaluated using a published dataset for 10 additional drugs and found to yield intrinsic clearance data comparable to the previously reported values. LESA provides a convenient and rapid method to determine the influence of microsome binding on intrinsic clearance in a single assay.

Address correspondence to: Ralph Laufer, Department of Pharmacology, IRBM, MRL Rome, Via Pontina Km 30.600, 00040 Pomezia (RM), Italy. E-mail: Ralph_Laufer{at}Merck.com




This article has been cited by other articles:


Home page
 Drug Metab. Dispos.Home page
S. S. De Buck, V. K. Sinha, L. A. Fenu, M. J. Nijsen, C. E. Mackie, and R. A. H. J. Gilissen
Prediction of Human Pharmacokinetics Using Physiologically Based Modeling: A Retrospective Analysis of 26 Clinically Tested Drugs
Drug Metab. Dispos., October 1, 2007; 35(10): 1766 - 1780.
[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.