Pharmaceutical Research

, Volume 24, Issue 12, pp 2171–2186

An In Silico Transwell Device for the Study of Drug Transport and Drug–Drug Interactions

  • Lana X. Garmire
  • David G. Garmire
  • C. Anthony Hunt
Research Paper

Abstract

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 Å) 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.

Key words

agent-based modeling discrete event drug transport drug–drug interaction emergent properties simulation 

Abbreviations

CYP

a P450 enzyme

ISTD

in silico transwell device

MW

molecular weight

PCP

physicochemical properties

PRN

pseudorandom number

SM

supplementary material

TD

transwell device

Supplementary material

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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Lana X. Garmire
    • 1
  • David G. Garmire
    • 2
  • C. Anthony Hunt
    • 3
  1. 1.Graduate Group in Comparative BiochemistryUniversity of CaliforniaBerkeleyUSA
  2. 2.The Berkeley Sensor and Actuator CenterUC BerkeleyBerkeleyUSA
  3. 3.BioSystems Group and the UCSF/UCB Joint Graduate Group in Bioengineering, Department of Biopharmaceutical SciencesUniversity of CaliforniaSan FranciscoUSA

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