Pharmaceutical Research

, Volume 23, Issue 3, pp 493–505

Mechanistic Study of the Cellular Interplay of Transport and Metabolism Using the Synthetic Modeling Method

Research Paper

Purpose

The aims of this study were 1) to demonstrate a new modeling strategy that uses experimental computational models built by the synthetic method and 2) to study the consequences of spatial alignment, or lack thereof, of P-glycoprotein (Pgp) and CYP3A4 on the transport and metabolism of drug-like compounds and the influence of competitive inhibition by metabolites on the transport and metabolism of those compounds.

Methods

The synthetic method of modeling and simulation was used to construct discrete-event, discrete-space models. Within a framework designed for experimentation, object-oriented software components were assembled into devices representing the efflux transport and metabolism mechanisms within cell monolayers in Caco-2 transwell systems.

Results

Conditions for transport and metabolism synergism (and lack thereof) were identified. Simulations showed how spatial alignment altered the coordinated influences of Pgp and CYP3A4 on absorption of a series of drug-like compounds. Within those experiments, when the metabolites were also substrates of Pgp, the metabolite levels produced were insufficient to give evidence of a competitive inhibitory effect on either transport or metabolism.

Conclusions

The results provide evidence of the potential value of using this class of models to improve our understanding of how complex cellular processes influence the transport and absorption of compounds, and the consequences of interventions.

Key Words

agent-based modeling CYP3A4 drug absorption P-glycoprotein simulation 

Abbreviations

A

apical

ANOVA

analysis of variance

B

basolateral

cyp

the in silico counterpart to CYP3A4

ER

extraction ratio

ISTS

in silico transwell system

Pgp

P-glycoprotein

pgp

the in silico counterpart to P-glycoprotein

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Copyright information

© Springer Science + Business Media, Inc. 2006

Authors and Affiliations

  1. 1.The UCSF/UCB Joint Graduate Group in BioengineeringUniversity of CaliforniaBerkeleyUSA
  2. 2.Department of Biopharmaceutical Sciences, Biosystems GroupUniversity of CaliforniaSan FranciscoUSA

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