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Research ArticleArticle

Predicting Metabolic Clearance for Drugs That Are Actively Transported into Hepatocytes: Incubational Binding as a Consequence of in Vitro Hepatocyte Concentration Is a Key Factor

Pär Nordell, Petter Svanberg, James Bird and Ken Grime
Drug Metabolism and Disposition April 2013, 41 (4) 836-843; DOI: https://doi.org/10.1124/dmd.112.050377
Pär Nordell
Respiratory and Inflammation DMPK, AstraZeneca R&D, Mölndal, Sweden
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Petter Svanberg
Respiratory and Inflammation DMPK, AstraZeneca R&D, Mölndal, Sweden
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James Bird
Respiratory and Inflammation DMPK, AstraZeneca R&D, Mölndal, Sweden
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Ken Grime
Respiratory and Inflammation DMPK, AstraZeneca R&D, Mölndal, Sweden
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Abstract

Incubational binding or the fraction of drug unbound in an in vitro incubation, fuinc, is an important parameter to predict or measure in the pursuit of accurate clearance predictions from in vitro data. Here we describe a method for fuinc determination directly in the hepatocyte intrinsic clearance (CLint) assay with emphasis on compounds that are actively transported into hepatocytes, hypothesizing that for such compounds the typical protocol of 1 million hepatocytes/ml systematically underestimates the maximum attainable unbound intracellular drug concentration. Using the transporter substrate atorvastatin as a test compound, incubations were performed and a mathematical model applied to describe metabolism, distribution, and binding at different hepatocyte concentrations. From these investigations it was evident that, since binding is more extensive intracellularly than in the medium, increased partitioning into the cellular volume, due to active uptake, increases the total amount of atorvastatin bound in the incubation. Consequently, a significant lowering of the hepatocyte concentration impacts the free drug concentration in the incubation and increases the observed rate of metabolism and therefore observed CLint (that is, when viewed from the media drug concentration). The applicability of the findings was tested for a series of 11 actively transported zwitterions for which standard rat hepatocyte metabolic CLint data (1 million cells/ml incubation) poorly predicted in vivo clearance (average fold error of 5.4). Using metabolic CLint determined at a lower hepatocyte concentration (0.125 million cells/ml) considerably improved clearance predictions (average fold error of 2.3).

Footnotes

  • dx.doi.org/ 10.1124/dmd.112.050377.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Received November 28, 2012.
  • Accepted January 30, 2013.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (4)
Drug Metabolism and Disposition
Vol. 41, Issue 4
1 Apr 2013
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Research ArticleArticle

A Method to Accurately Assay CLint of Actively Transported Drugs

Pär Nordell, Petter Svanberg, James Bird and Ken Grime
Drug Metabolism and Disposition April 1, 2013, 41 (4) 836-843; DOI: https://doi.org/10.1124/dmd.112.050377

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Research ArticleArticle

A Method to Accurately Assay CLint of Actively Transported Drugs

Pär Nordell, Petter Svanberg, James Bird and Ken Grime
Drug Metabolism and Disposition April 1, 2013, 41 (4) 836-843; DOI: https://doi.org/10.1124/dmd.112.050377
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