Aspirin and Salicylate circulate in the plasma and are converted to salicylurate in liver mitochondria prior to clearance, mainly as salicylurate.

Description

Diverse data sets can yield reliable information through
mechanistic modeling: salicylic acid clearance
                    by
     Raymond GM and Bassingthwaighte JB. 

NSR Model 369 provides 3 models each fitting of data from the
 same three sources as here:
 1. Exponential Washout or Half-life for clearance
 2. Michaelis-Menten reaction in plasma.
 3. Enzyme kinetics, fully reversible reactions for substrate and product 

This MODEL 377 CONSIDERS THE REACTION TO OCCUR IN MITOCHONDRIA (LIVER)
BUT CLEARNCE TO BE FROM THE BLOOD. The mito volume is set to 1/1000 of the 
blood volume, so compared to the Model 369 solutions the kinetic parameters 
are the same, except that a large Etot and therefore Vmax in the mito
is used to give the same total reaction capacity.

                kon1       koff2
       S + E   ------> SE  ------> E + P
              <------     <------
                koff1      kon2

Figure 1: Fig01_DataPlot:
The three sets of digitized data from the references
are in DataSets lowdose, middose, and high dose. These files
will be referenced in the plots and used for optimizing
parameters. 

Figure 2: EnzSatur:
 Plotted versus time are the blood and intramitochondrial concns
and the fractional saturation of the enzyme inside the mito. The blood data
are shown by the symbols.

Figure 3: FitEnzMito:
 For each dose level the plasma concn (red) and the intramito concn (blue)
are plotted against the blood data for the three data sets. The concn of
product is green: solid lines for inside the mito and dashed lines for blood.
Product blood levels are lower because the only clearance is from the blood.
Salicylate blood levels are always higher than mito levels since direct 
salicylate clearance from blood is low, and inside the mito it is being 
converted to product salicylurate. Parameters as in Table 3, right 3 columns
of Raymond and Bassingthwaighte Brit J Pharm Res 2015.

Equations

None.

The equations for this model may be viewed by running the JSim model applet and clicking on the Source tab at the bottom left of JSim's Run Time graphical user interface. The equations are written in JSim's Mathematical Modeling Language (MML). See the Introduction to MML and the MML Reference Manual. Additional documentation for MML can be found by using the search option at the Physiome home page.