Abstract
Prediction of intestinal availability (FG), in conjunction with hepatic metabolism, is of considerable importance in drug disposition to assess oral clearance and liability to drug-drug interactions. In the current study, FG predictions were performed within a physiologically based pharmacokinetic (PBPK) model using in vitro permeability and clearance data. The prediction success was assessed in comparison with the QGut model. In addition, apparent oral clearance values, predicted using the PBPK model, were compared with in vivo observations from meta-analyses. Finally, unbound intrinsic clearance values (CLuint) were determined for 12 CYP3A substrates in eight individual human jejunal microsome (HJM) samples to assess interindividual variability in intestinal intrinsic clearance and subsequent FG predictions. Overall, the PBPK model improved FG predictions in comparison with the QGut model; this was apparent by a reduced bias and increased precision. In particular, FG predictions of indinavir, saquinavir, and terfenadine were model-dependent. The predicted oral clearance values of the drugs investigated ranged from 8.79 to 6320 l/h for tacrolimus and simvastatin, respectively, and were overall within 3-fold of the observed data with the exception of indinavir, atorvastatin, and buspirone. The individual HJM CLuint values ranged from 17 to 14,000 μl · min−1 · mg−1 for atorvastatin and saquinavir, respectively, and corresponding interindividual variability in CLuint estimates ranged from 41 to 67%. These in vitro data resulted in predicted FG values ranging from 0.03 to 0.94 for simvastatin and indinavir, respectively. The largest interindividual variability of FG was predicted for terfenadine (65%) in contrast with the low variability in the case of indinavir (3%).
Footnotes
This work was supported by a consortium of pharmaceutical companies (GlaxoSmithKline, Lilly, Novartis, Pfizer, and Servier) within the Centre for Applied Pharmacokinetic Research at the University of Manchester.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.111.039248.
↵ The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- FG
- intestinal availability
- QGut
- hybrid parameter of enterocytic blood flow and drug permeability
- PBPK
- physiologically based pharmacokinetic
- HJM
- human jejunal microsomes
- LC
- liquid chromatography
- MS/MS
- tandem mass spectrometry
- MDCK-MDR1
- Madin-Darby canine kidney cells transfected with human MDR1 gene
- CL
- clearance
- fu
- fraction unbound
- HIM
- human intestinal microsomes
- HLM
- human liver microsomes
- CV
- coefficient of variation.
- Received March 2, 2011.
- Accepted June 1, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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