title: The importance of villous physiology and morphology in mechanistic physiologically-based pharmacokinetic models.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Preclinical Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania, 19406, USA, emile.p.chen@gsk.com.
authors.forename: Emile P
authors.initials: EP
authors.lastname: Chen
authors.forename: Guoying
authors.initials: G
authors.lastname: Tai
authors.forename: Harma
authors.initials: H
authors.lastname: Ellens
mesh_terms: D000328:Adult; D000368:Aged; D003198:Computer Simulation; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004347:Drug Interactions; D020895:Enterocytes / Q000378:metabolism; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics*; D008875:Middle Aged; D008954:Models, Biological; D010539:Permeability
chemical_list: C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam