Physiologically based pharmacokinetic modeling of intestinal first-pass metabolism of CYP3A substrates with high intestinal extractionCitation formats

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Physiologically based pharmacokinetic modeling of intestinal first-pass metabolism of CYP3A substrates with high intestinal extraction. / Gertz, Michael; Houston, J. Brian; Galetin, Aleksandra.

In: Drug Metabolism and Disposition, Vol. 39, No. 9, 09.2011, p. 1633-1642.

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@article{cd03a640d61d4d66b48681acada7cc57,
title = "Physiologically based pharmacokinetic modeling of intestinal first-pass metabolism of CYP3A substrates with high intestinal extraction",
abstract = "Prediction of intestinal availability (F G), 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, F G 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 Q Gut 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 (CLu int) were determined for 12 CYP3A substrates in eight individual human jejunal microsome (HJM) samples to assess interindividual variability in intestinal intrinsic clearance and subsequent F G predictions. Overall, the PBPK model improved FG predictions in comparison with the Q Gut model; this was apparent by a reduced bias and increased precision. In particular, F G predictions of indinavir, saquinavir, and terfenadine were modeldependent. 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 CLu int values ranged from 17 to 14,000 μl·min -1·mg -1 for atorvastatin and saquinavir, respectively, and corresponding interindividual variability in CLu int estimates ranged from 41 to 67{\%}. These in vitro data resulted in predicted F G values ranging from 0.03 to 0.94 for simvastatin and indinavir, respectively. The largest interindividual variability of F G was predicted for terfenadine (65{\%}) in contrast with the low variability in the case of indinavir (3{\%}). Copyright {\circledC} 2011 by The American Society for Pharmacology and Experimental Therapeutics.",
author = "Michael Gertz and Houston, {J. Brian} and Aleksandra Galetin",
year = "2011",
month = "9",
doi = "10.1124/dmd.111.039248",
language = "English",
volume = "39",
pages = "1633--1642",
journal = "Drug Metabolism and Disposition -Bethesda-",
issn = "0090-9556",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "9",

}

RIS

TY - JOUR

T1 - Physiologically based pharmacokinetic modeling of intestinal first-pass metabolism of CYP3A substrates with high intestinal extraction

AU - Gertz, Michael

AU - Houston, J. Brian

AU - Galetin, Aleksandra

PY - 2011/9

Y1 - 2011/9

N2 - Prediction of intestinal availability (F G), 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, F G 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 Q Gut 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 (CLu int) were determined for 12 CYP3A substrates in eight individual human jejunal microsome (HJM) samples to assess interindividual variability in intestinal intrinsic clearance and subsequent F G predictions. Overall, the PBPK model improved FG predictions in comparison with the Q Gut model; this was apparent by a reduced bias and increased precision. In particular, F G predictions of indinavir, saquinavir, and terfenadine were modeldependent. 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 CLu int values ranged from 17 to 14,000 μl·min -1·mg -1 for atorvastatin and saquinavir, respectively, and corresponding interindividual variability in CLu int estimates ranged from 41 to 67%. These in vitro data resulted in predicted F G values ranging from 0.03 to 0.94 for simvastatin and indinavir, respectively. The largest interindividual variability of F G was predicted for terfenadine (65%) in contrast with the low variability in the case of indinavir (3%). Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics.

AB - Prediction of intestinal availability (F G), 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, F G 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 Q Gut 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 (CLu int) were determined for 12 CYP3A substrates in eight individual human jejunal microsome (HJM) samples to assess interindividual variability in intestinal intrinsic clearance and subsequent F G predictions. Overall, the PBPK model improved FG predictions in comparison with the Q Gut model; this was apparent by a reduced bias and increased precision. In particular, F G predictions of indinavir, saquinavir, and terfenadine were modeldependent. 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 CLu int values ranged from 17 to 14,000 μl·min -1·mg -1 for atorvastatin and saquinavir, respectively, and corresponding interindividual variability in CLu int estimates ranged from 41 to 67%. These in vitro data resulted in predicted F G values ranging from 0.03 to 0.94 for simvastatin and indinavir, respectively. The largest interindividual variability of F G was predicted for terfenadine (65%) in contrast with the low variability in the case of indinavir (3%). Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics.

U2 - 10.1124/dmd.111.039248

DO - 10.1124/dmd.111.039248

M3 - Article

VL - 39

SP - 1633

EP - 1642

JO - Drug Metabolism and Disposition -Bethesda-

JF - Drug Metabolism and Disposition -Bethesda-

SN - 0090-9556

IS - 9

ER -