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The AAPS Journal

, Volume 18, Issue 3, pp 589–604 | Cite as

Gut Wall Metabolism. Application of Pre-Clinical Models for the Prediction of Human Drug Absorption and First-Pass Elimination

  • Christopher R. Jones
  • Oliver J. D. Hatley
  • Anna-Lena Ungell
  • Constanze Hilgendorf
  • Sheila Annie Peters
  • Amin Rostami-Hodjegan
Review Article

Abstract

Quantifying the multiple processes which control and modulate the extent of oral bioavailability for drug candidates is critical to accurate projection of human pharmacokinetics (PK). Understanding how gut wall metabolism and hepatic elimination factor into first-pass clearance of drugs has improved enormously. Typically, the cytochrome P450s, uridine 5′-diphosphate-glucuronosyltransferases and sulfotransferases, are the main enzyme classes responsible for drug metabolism. Knowledge of the isoforms functionally expressed within organs of first-pass clearance, their anatomical topology (e.g. zonal distribution), protein homology and relative abundances and how these differ across species is important for building models of human metabolic extraction. The focus of this manuscript is to explore the parameters influencing bioavailability and to consider how well these are predicted in human from animal models or from in vitro to in vivo extrapolation. A unique retrospective analysis of three AstraZeneca molecules progressed to first in human PK studies is used to highlight the impact that species differences in gut wall metabolism can have on predicted human PK. Compared to the liver, pharmaceutical research has further to go in terms of adopting a common approach for characterisation and quantitative prediction of intestinal metabolism. A broad strategy is needed to integrate assessment of intestinal metabolism in the context of typical DMPK activities ongoing within drug discovery programmes up until candidate drug nomination.

Keywords

animal models drug-metabolising enzymes first-pass oral clearance gut wall metabolism oral bioavailability 

Notes

Acknowledgments

This work was contributed to the OrBiTo project (http://www.imi.europa.eu/content/orbito) as side ground.

O.J.D.Hatley was funded by a PhD grant awarded through the CASE award scheme, receiving support from both the MRC and AstraZeneca.

All in vivo work conducted within AstraZeneca was subject to internal ethical review and conducted in accordance with Home Office requirements under the Animals Scientific Procedures Act (1986).

Supplementary material

12248_2016_9889_Fig5_ESM.gif (4 kb)
Figure S1

Structure features of AZ12470164. (GIF 3 kb)

12248_2016_9889_MOESM1_ESM.tif (153 kb)
High resolution image (TIF 153 kb)
12248_2016_9889_Fig6_ESM.gif (4 kb)
Figure S2

Structure of AZD1283. (GIF 4 kb)

12248_2016_9889_MOESM2_ESM.tif (162 kb)
High resolution image (TIF 162 kb)
12248_2016_9889_Fig7_ESM.gif (4 kb)
Figure S3

Structure of AZD7009. (GIF 3 kb)

12248_2016_9889_MOESM3_ESM.tif (152 kb)
High resolution image (TIF 152 kb)
12248_2016_9889_Fig8_ESM.gif (19 kb)
Figure S4

Physiologically based PK simulations of PK profiles of AZD7009 in rats. Simulations of (a) IV and (b) oral profiles against the observed data from different animals, reprinted with permission (100). (GIF 18 kb)

12248_2016_9889_MOESM4_ESM.tif (1 mb)
High resolution image (TIF 1064 kb)
12248_2016_9889_Fig9_ESM.gif (36 kb)
Figure S5

Physiologically based PK simulations of PK profiles of AZD7009 in humans. (a) Simulation of the intravenous profile without enterohepatic recirculation. (b) Simulation of the intravenous profile with inclusion of enterohepatic recirculation. (c) Simulated oral profile against the observed when intestinal loss was not considered; the permeability used was 5.8 cm/s. (d) Simulated oral profile against the observed when intestinal loss was not considered; the permeability used was 1.9 cm/s. (e) Simulation of the oral profile with intestinal loss rate constants introduced and refinement with enterohepatic recirculation. (f) Simulation of the oral profile excluding enterohepatic recirculation and including intestinal loss. (g) Simulation of the oral profile including enterohepatic recirculation and excluding intestinal loss. Reprinted with permission (100). (GIF 35 kb)

12248_2016_9889_MOESM5_ESM.tif (2.2 mb)
High resolution image (TIF 2300 kb)
12248_2016_9889_MOESM6_ESM.pdf (11 kb)
Table S1 AZD7009 summary data used in physiologically based PK simulations, reprinted with permission (100). Values are expressed as mean ± SD. (PDF 11 kb)
12248_2016_9889_MOESM7_ESM.pdf (29 kb)
Table S2 Metabolite: parent drug (M/P) ratios in humans for AZD7009. Reprinted with permission (100). (PDF 28 kb)

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Copyright information

© American Association of Pharmaceutical Scientists 2016

Authors and Affiliations

  • Christopher R. Jones
    • 1
    • 8
  • Oliver J. D. Hatley
    • 2
  • Anna-Lena Ungell
    • 3
    • 4
  • Constanze Hilgendorf
    • 5
  • Sheila Annie Peters
    • 6
  • Amin Rostami-Hodjegan
    • 7
  1. 1.Oncology Innovative Medicines DMPKAstraZenecaCheshireUK
  2. 2.Simcyp Limited (a Certara Company)Blades Enterprise CentreSheffieldUK
  3. 3.CVMD Innovative Medicines DMPKAstraZenecaMölndalSweden
  4. 4.Investigative ADME, Non Clinical DevelopmentUCB New Medicines, BioPharma SPRLBraine A’lleudBelgium
  5. 5.Drug Safety and Metabolism DMPKAstraZenecaMölndalSweden
  6. 6.Modelling and Simulation, Respiratory, Inflammation and Autoimmunity Innovative Medicines DMPKAstraZenecaMölndalSweden
  7. 7.Centre for Applied Pharmacokinetic Research, Manchester School of PharmacyUniversity of ManchesterManchesterUK
  8. 8.Heptares Therapeutics LtdWelwyn Garden CityUK

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