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

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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.

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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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Acknowledgments

This research was funded in part by the CDH Research Foundation (R21CDH00101; CAH is a trustee of the CDH Research Foundation) and CAH. We thank Glen Ropella for his many contributions; we thank Robert Spear and Betty-ann Hoener; we also thank the members of the Biosystems Group for helpful discussion and commentary,with special thanks going to Jesse Engelberg, Pearl Johnson, Sean Kim, Tai Ning Lam, Amina Qutub, and JonTang.

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Authors and Affiliations

  1. The UCSF/UCB Joint Graduate Group in Bioengineering, University of California, Berkeley, California, USA

    Yu Liu & C. Anthony Hunt

  2. Department of Biopharmaceutical Sciences, Biosystems Group, University of California, 513 Parnassus Avenue, S-926, San Francisco, California, 94143-0446, USA

    C. Anthony Hunt

Authors
  1. Yu Liu
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  2. C. Anthony Hunt
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Correspondence to C. Anthony Hunt.

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Liu, Y., Hunt, C.A. Mechanistic Study of the Cellular Interplay of Transport and Metabolism Using the Synthetic Modeling Method. Pharm Res 23, 493–505 (2006). https://doi.org/10.1007/s11095-006-9505-4

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  • DOI: https://doi.org/10.1007/s11095-006-9505-4

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