Mechanistic study of the cellular interplay of transport and metabolism using the synthetic modeling method.
OBJECTIVE
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.
Liu
Yu
Y
The UCSF/UCB Joint Graduate Group in Bioengineering, University of California, Berkeley, California, USA.
Hunt
C Anthony
CA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry / Q000378:metabolism*; D018938:Caco-2 Cells; D003198:Computer Simulation; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007408:Intestinal Absorption; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D014162:Transfection
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human