P-glycoprotein, a @entity1 multidrug resistance transporter, has been extensively studied due to its importance to @entity1 health and disease. In order to understand transport kinetics via @entity7895 , confluent cell monolayers overexpressing @entity7895 are widely used. The purpose of this study is to obtain the mass action elementary rate constants for @entity7895 's transport and to functionally characterize members of @entity7895 's network, i.e., other transporters that transport @entity7895 substrates in @entity1262 confluent cell monolayers and are essential to the net substrate flux. Transport of a range of concentrations of @entity5192 , @entity3062 , @entity5126 and @entity6838 across the confluent monolayer of cells was measured in both directions, apical to basolateral and basolateral to apical. We developed a global optimization algorithm using the Particle Swarm method that can simultaneously fit all datasets to yield accurate and exhaustive fits of these elementary rate constants. The statistical sensitivity of the fitted values was determined by using 24 identical replicate fits, yielding simple averages and standard deviations for all of the kinetic parameters, including the efflux active @entity7895 surface density. Digoxin required additional basolateral and apical transporters, while @entity3062 required just a basolateral tranporter. The data were better fit by assuming bidirectional transporters, rather than active importers, suggesting that they are not @entity11092 or active OATP transporters. The @entity7895 efflux rate constants for @entity5126 and digoxin were about 3-fold smaller than reported @entity855 hydrolysis rate constants from @entity7895 proteoliposomes. This suggests a roughly 3   1 stoichiometry between @entity855 hydrolysis and @entity7895 transport for these two drugs. The fitted values of the elementary rate constants for these @entity7895 substrates support the hypotheses that the selective pressures on @entity7895 are to maintain a broad substrate range and to keep xenobiotics out of the cytosol, but not out of the apical membrane.

Fitting the elementary rate constants of the P-gp transporter network in the XXXX -MDCK confluent cell monolayer using a particle swarm algorithm.

@entity1 :: ('9606', 'Species') :: ['human'] @entity1262 :: ('5243', 'Gene') :: ['hMDR1-MDCKII'] @entity5192 :: ('MESH:C095108', 'Chemical') :: ['amprenavir'] @entity855 :: ('MESH:D000255', 'Chemical') :: ['ATP'] @entity6838 :: ('MESH:D004077', 'Chemical') :: ['digoxin'] @entity11092 :: ('4363', 'Gene') :: ['MRP'] @entity5126 :: ('MESH:D011802', 'Chemical') :: ['quinidine'] @entity7895 :: ('283871', 'Gene') :: ['P-gp'] @entity3062 :: ('MESH:D008139', 'Chemical') :: ['loperamide']
@entity1262 :: (5243,Gene) :: ['hMDR1']
