Maximal efflux velocity

The maximal efflux velocity (Vm) depended on the P-gp secretion transporter expression level. A baseline value was taken to be the expression level in ileum (Vmi). The value of maximal velocity in duodenum (Vmn) and jejunum (Vmj) was computed from the baseline value and a correction factor (Ej), based on... 

Vmaxiinjlux or efflux) = Maximal velocity of the saturable transporter Km(injiux or efflux) = Michaelis constant for the saturable transporter Q = Concentration of drug inside the lumen of the intestine CSnt(i) = Concentration of drug inside the enterocyte in compartment i... 

More difficult in BLMs, refined HPTS assays exist to address the special cases of selective transport of protons [11] and electrons [17] in LUVs. In the conventional HPTS assay (Fig. 11.5c), the apparent activity of proton channels decreases with increasing proton selectivity because the rate ofthe disfavored cation (M ) influx influences the detected velocity more than the favored proton efflux. Disfavored potassium influx can, however, be accelerated with the potassium carrier vaiinomycin (Fig. 11.8). Increasing activity in the presence of vaiinomycin identifies proton channels with H > K+ selectivity being at least as high as the maximal measurable increase (in unpolarized LUVs of course, compare Section 11.3.4). Important controls include evidence for low enough vaiinomycin concentrations to exclude activity without the proton channel (due to disfavored H+ efflux). The proton carrier FCCP is often used as complementary additive to confirm M+ > H+ selectivity (e.g. amphotericin B). 

Third, the equations employed in a PBPK model should be consistent with the state of knowledge or biologically plausible hypotheses of the mechanisms of ADME for the particular chemical. In this regard, the uptake of chemicals in systemic circulation is described as either a diffusion-limited or perfusion-limited process (Gerlowski and Jain 1983), and metabolic clearance in individual tissues or tissue groups is described using a maximal velocity and Michaelis constant, intrinsic clearance, or hepatic extraction ratio (Krishnan and Andersen 2007). The mass balance differential equations accounting for uptake clearance, efflux clearance, and metabolic clearance are formulated as a function of identifiable input parameters (Table 21.1). 

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