title: An in silico transwell device for the study of drug transport and drug-drug interactions.
abstract: OBJECTIVE
  Validate and exemplify a discrete, componentized, in silico, transwell device (ISTD) capable of mimicking the in vitro passive transport properties of compounds through cell monolayers. Verify its use for studying drug-drug interactions.
  
  
  METHODS
  We used the synthetic modeling method. Specialized software components represented spatial and functional features including cell components, semi-porous tight junctions, and metabolizing enzymes. Mobile components represented drugs. Experiments were conducted and analyzed as done in vitro.
  
  
  RESULTS
  Verification experiments provided data analogous to those in the literature. ISTD parameters were tuned to simulate and match in vitro urea transport data; the objects representing tight junction (effective radius of 6.66 A) occupied 0.066% of the surface area. That ISTD was then tuned to simulate pH-dependent, in vitro alfentanil transport properties. The resulting ISTD predicted the passive transport properties of 14 additional compounds, individually and all together in one in silico experiment. The function of a two-site enzymatic component was cross-validated with a kinetic model and then experimentally validated against in vitro benzyloxyresorufin metabolism data. Those components were used to exemplify drug-drug interaction studies.
  
  
  CONCLUSIONS
  The ISTD is an example of a new class of simulation models capable of realistically representing complex drug transport and drug-drug interaction phenomena.
authors: Graduate Group in Comparative Biochemistry, University of California, Berkeley, California, USA.
authors: Lana X
authors: LX
authors: Garmire
authors: David G
authors: DG
authors: Garmire
authors: C Anthony
authors: CA
authors: Hunt
mesh_terms: D015760:Alfentanil / Q000378:metabolism; D000701:Analgesics, Opioid / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D020134:Catalytic Domain; D002462:Cell Membrane / Q000378:metabolism*; D003198:Computer Simulation; D004058:Diffusion; D004353:Drug Evaluation, Preclinical / Q000295:instrumentation*; D004347:Drug Interactions; D004798:Enzymes / Q000378:metabolism; D004867:Equipment Design; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008954:Models, Biological; D010078:Oxazines / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D015203:Reproducibility of Results; D012984:Software; D013678:Technology, Pharmaceutical / Q000295:instrumentation*; D019108:Tight Junctions / Q000378:metabolism; D014508:Urea / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D004798:Enzymes; D010078:Oxazines; D004364:Pharmaceutical Preparations; D015760:Alfentanil; C057754:benzyloxyresorufin; D014508:Urea
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