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Pharm Res. 2014 Feb;31(2):305-21. doi: 10.1007/s11095-013-1161-x. Epub 2013 Aug 30.

The importance of villous physiology and morphology in mechanistic physiologically-based pharmacokinetic models.

Author information

1
Department of Preclinical Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania, 19406, USA, emile.p.chen@gsk.com.

Abstract

PURPOSE:

Existing PBPK models incorporating intestinal first-pass metabolism account for effect of drug permeability on accessible absorption surface area by use of "effective" permeability, P eff , without adjusting number of enterocytes involved in absorption or proportion of intestinal CYP3A involved in metabolism. The current model expands on existing models by accounting for these factors.

METHODS:

The PBPK model was developed using SAAM II. Midazolam clinical data was generated at GlaxoSmithKline.

RESULTS:

The model simultaneously captures human midazolam blood concentration profile and previously reported intestinal availability, using values for CYP3A CLu int , permeability and accessible surface area comparable to literature data. Simulations show: (1) failure to distinguish absorbing from non-absorbing enterocytes results in overestimation of intestinal metabolism of highly permeable drugs absorbed across the top portion of the villous surface only; (2) first-pass extraction of poorly permeable drugs occurs primarily in enterocytes, drugs with higher permeability are extracted by enterocytes and hepatocytes; (3) CYP3A distribution along crypt-villous axes does not significantly impact intestinal metabolism; (4) differences in permeability of perpetrator and victim drugs results in their spatial separation along the villous axis and intestinal length, diminishing drug-drug interaction magnitude.

CONCLUSIONS:

The model provides a useful tool to interrogate intestinal absorption/metabolism of candidate drugs.

PMID:
23990312
DOI:
10.1007/s11095-013-1161-x
[Indexed for MEDLINE]

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