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Pharm Res. 2007 Dec;24(12):2171-86. Epub 2007 Aug 17.

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

Author information

1
Graduate Group in Comparative Biochemistry, University of California, Berkeley, California, USA.

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 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.

PMID:
17703347
DOI:
10.1007/s11095-007-9391-4
[Indexed for MEDLINE]

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