An in silico transwell device for the study of drug transport and drug-drug interactions

Pharm Res. 2007 Dec;24(12):2171-86. doi: 10.1007/s11095-007-9391-4. Epub 2007 Aug 17.


Purpose: 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Alfentanil / metabolism
  • Analgesics, Opioid / metabolism
  • Animals
  • Biological Transport*
  • Catalytic Domain
  • Cell Membrane / metabolism*
  • Computer Simulation
  • Diffusion
  • Drug Evaluation, Preclinical / instrumentation*
  • Drug Interactions*
  • Enzymes / metabolism
  • Equipment Design
  • Humans
  • Hydrogen-Ion Concentration
  • Kinetics
  • Models, Biological
  • Oxazines / metabolism
  • Pharmaceutical Preparations / metabolism*
  • Reproducibility of Results
  • Software*
  • Technology, Pharmaceutical / instrumentation*
  • Tight Junctions / metabolism
  • Urea / metabolism


  • Analgesics, Opioid
  • Enzymes
  • Oxazines
  • Pharmaceutical Preparations
  • Alfentanil
  • benzyloxyresorufin
  • Urea