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The Importance of Villous Physiology and Morphology in Mechanistic Physiologically-Based Pharmacokinetic Models

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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.

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Abbreviations

AUC :

area under the curve

CL :

clearance

F :

oral bioavailability

F g :

intestinal availability

F h :

hepatic availability

f ub :

free fraction in blood

f ue :

free fraction in enterocyte

f uh :

free fraction in hepatocyte

HLQ :

higher limit of quantitation

ICRP:

the International Commission on Radiological Protection

LC/MS/MS:

high performance liquid chromatography with tandem mass spectrometry

LLQ :

lower limit of quantitation

PBPK:

physiologically-based pharmacokinetics model

P eff :

effective permeability

P-gp:

P-glycoprotein

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Authors and Affiliations

  1. Department of Preclinical Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania, 19406, USA

    Emile P. Chen, Guoying Tai & Harma Ellens

  2. GlaxoSmithKline, 709 Swedeland Rd. UW2720, King of Prussia, Pennsylvania, 19473, USA

    Emile P. Chen

Authors
  1. Emile P. Chen
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  2. Guoying Tai
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  3. Harma Ellens
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Correspondence to Emile P. Chen.

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Chen, E.P., Tai, G. & Ellens, H. The Importance of Villous Physiology and Morphology in Mechanistic Physiologically-Based Pharmacokinetic Models. Pharm Res 31, 305–321 (2014). https://doi.org/10.1007/s11095-013-1161-x

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  • DOI: https://doi.org/10.1007/s11095-013-1161-x

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