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Metabolite concentration time data #229

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samitganguly opened this Issue Sep 29, 2018 · 2 comments

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@samitganguly

samitganguly commented Sep 29, 2018

Hi,

I have the Km and Vmax values for the parent metabolism using a tissue homogenate as well as recombinant enzyme. From a separate paper, I found the parent and metabolite time-concentration profile and I wanted to simulate for both of them together in PKSim. The parent simulation works great. But, I am not being able to get the metabolite profile.
Can you please help with:

  1. How to add a metabolite profile?
    I have added the enzyme in individual and compound. Created a metabolite compound based on only known parameter - its molecular weight and guesstimated the other Physicochemical parameters.

  2. This is mainly kidney enzyme and also present in other tissues (not so much in liver). How will that be accounted in the simulation? When I add metabolizing enzyme, is PKSim only considering metabolism for the fraction expressed in liver? If yes, how can I address this?

  3. I tried increasing the enzyme expression (individual expression and also in compound-expression-enzyme parameters); a 1000 fold increase in the expression also not sufficient to match the observed data. I also increased Vmax, the same observation.
    Am I missing something or doing it absolutely incorrectly?

Regards
Samit Ganguly

@Aedginto

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Aedginto commented Oct 11, 2018

  1. Make sure that when creating your compound, in the ADME section, for the enzymatic process that is creating the metabolite, that you select the metabolite in the same window.
  2. When you create an Individual and add a metabolizing enzyme, you can add it by hand or using the gene database (https://docs.open-systems-pharmacology.org/working-with-pk-sim-r/pk-sim-r-documentation/pk-sim-expression-data#the-workflow) that will populate the relative expression in each organ based on e.g. rtPCR results. If by hand, and all in kidney, put a 1 next to kidney and all metabolism by this enzyme will occur only in kidney.
  3. If you did item 2 above and just put the enzyme in kidney, you may be reaching a blood flow limitation and therefore it won't matter how much enzyme is in there, extraction ratio is 1 and clearance by that organ is blood flow limited. It is likely that the enzyme resides in more than just kidney....try finding it with the gene database (if human) instead.
    Take care,
    Andrea
@samitganguly

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samitganguly commented Oct 11, 2018

Thank you Andrea!

Regards
Samit

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