QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: dmd.105.004259v1 33/9/1304    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Riley, R. J. Articles by Austin, R. P. Search for Related Content PubMed PubMed Citation Articles by Riley, R. J. Articles by Austin, R. P.

A UNIFIED MODEL FOR PREDICTING HUMAN HEPATIC, METABOLIC CLEARANCE FROM IN VITRO INTRINSIC CLEARANCE DATA IN HEPATOCYTES AND MICROSOMES

Department of Physical and Metabolic Science, AstraZeneca R&D Charnwood, Loughborough, Leicestershire, United Kingdom

The aim of this study was to evaluate a unified method for predicting human in vivo intrinsic clearance (CL_{int, in vivo}) and hepatic clearance (CL_h) from in vitro data in hepatocytes and microsomes by applying the unbound fraction in blood (fu_b) and in vitro incubations (fu_inc). Human CL_{int, in vivo} was projected using in vitro data together with biological scaling factors and compared with the unbound intrinsic clearance (CL_{int, ub, in vivo}) estimated from clinical data using liver models with and without the various fu terms. For incubations conducted with fetal calf serum (n = 14), the observed CL_{int, in vivo} was modeled well assuming fu_inc and fu_b were equivalent. CL_{int, ub, in vivo} was predicted best using both fu_b and fu_inc for other hepatocyte data (n = 56; r² = 0.78, p = 3.3 x 10^–19, average fold error = 5.2). A similar model for CL_{int, ub, in vivo} was established for microsomal data (n = 37; r² = 0.77, p = 1.2 x 10^–12, average fold error = 6.1). Using the model for CL_{int, ub, in vivo} (including a further empirical scaling factor), the CL_h in humans was also calculated according to the well stirred liver model for the most extensive dataset. CL_{int, in vivo} and CL_h were both predicted well using in vitro human data from several laboratories for acidic, basic, and neutral drugs. The direct use of this model using only in vitro human data to predict the metabolic component of CL_h is attractive, as it does not require extra information from preclinical studies in animals.

This article has been cited by other articles:

				S. W. Paine, A. J. Parker, P. Gardiner, P. J. H. Webborn, and R. J. Riley Prediction of the Pharmacokinetics of Atorvastatin, Cerivastatin, and Indomethacin Using Kinetic Models Applied to Isolated Rat Hepatocytes Drug Metab. Dispos., July 1, 2008; 36(7): 1365 - 1374. [Abstract] [Full Text] [PDF]

				R. S. Obach, F. Lombardo, and N. J. Waters Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 670 Drug Compounds Drug Metab. Dispos., July 1, 2008; 36(7): 1385 - 1405. [Abstract] [Full Text] [PDF]

				A. Rowland, D. J. Elliot, K. M. Knights, P. I. Mackenzie, and J. O. Miners The "Albumin Effect" and in Vitro-in Vivo Extrapolation: Sequestration of Long-Chain Unsaturated Fatty Acids Enhances Phenytoin Hydroxylation by Human Liver Microsomal and Recombinant Cytochrome P450 2C9 Drug Metab. Dispos., May 1, 2008; 36(5): 870 - 877. [Abstract] [Full Text] [PDF]

				M. Gertz, P. J. Kilford, J. B. Houston, and A. Galetin Drug Lipophilicity and Microsomal Protein Concentration as Determinants in the Prediction of the Fraction Unbound in Microsomal Incubations Drug Metab. Dispos., March 1, 2008; 36(3): 535 - 542. [Abstract] [Full Text] [PDF]

				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]

				M. G. Soars, K. Grime, J. L. Sproston, P. J. H. Webborn, and R. J. Riley Use of Hepatocytes to Assess the Contribution of Hepatic Uptake to Clearance in Vivo Drug Metab. Dispos., June 1, 2007; 35(6): 859 - 865. [Abstract] [Full Text] [PDF]

				A. Rowland, P. Gaganis, D. J. Elliot, P. I. Mackenzie, K. M. Knights, and J. O. Miners Binding of Inhibitory Fatty Acids Is Responsible for the Enhancement of UDP-Glucuronosyltransferase 2B7 Activity by Albumin: Implications for in Vitro-in Vivo Extrapolation J. Pharmacol. Exp. Ther., April 1, 2007; 321(1): 137 - 147. [Abstract] [Full Text] [PDF]

				H. S. Brown, M. Griffin, and J. B. Houston Evaluation of Cryopreserved Human Hepatocytes as an Alternative in Vitro System to Microsomes for the Prediction of Metabolic Clearance Drug Metab. Dispos., February 1, 2007; 35(2): 293 - 301. [Abstract] [Full Text] [PDF]

				J. Y. Chien, A. Lucksiri, C. S. Ernest II, J. C. Gorski, S. A. Wrighton, and S. D. Hall STOCHASTIC PREDICTION OF CYP3A-MEDIATED INHIBITION OF MIDAZOLAM CLEARANCE BY KETOCONAZOLE Drug Metab. Dispos., July 1, 2006; 34(7): 1208 - 1219. [Abstract] [Full Text] [PDF]

				D. Hallifax and J. B. Houston BINDING OF DRUGS TO HEPATIC MICROSOMES: COMMENT AND ASSESSMENT OF CURRENT PREDICTION METHODOLOGY WITH RECOMMENDATION FOR IMPROVEMENT Drug Metab. Dispos., April 1, 2006; 34(4): 724 - 726. [Full Text] [PDF]

				D. F. McGinnity, J. Tucker, S. Trigg, and R. J. Riley PREDICTION OF CYP2C9-MEDIATED DRUG-DRUG INTERACTIONS: A COMPARISON USING DATA FROM RECOMBINANT ENZYMES AND HUMAN HEPATOCYTES Drug Metab. Dispos., November 1, 2005; 33(11): 1700 - 1707. [Abstract] [Full Text] [PDF]