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enterocyte lysosomes trapping simulation #346

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wdzth opened this issue Jun 19, 2019 · 6 comments

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@wdzth
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commented Jun 19, 2019

need help! my drug, logp 3.8, pka 9.2 base, is considered to be trapping in enterocyte lysosomes when po adminstration, resulting tmax delayed to 4-8 h, how can i simulate this process in pk-sim?

@wdzth

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commented Jun 21, 2019

dear all,
can anyone help me?
best
zhang

@StephanSchaller

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commented Jun 21, 2019

Hi Zhang,

i guess it depends on how detailed you need this implemented.

A good workaround could be to introduce unspecific binding (to protein/phospholipids) in the GITract.
Either luminal or within mucosa.

For this, you just have to define a Protein Binding Partner (and its distribution) in the "Individual" building block and the corresponding binding mechanism in the "Compound" building block.

Anything more complex/detailed will require MoBi to implement.

Hope this helps,
Stephan

@wdzth

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commented Jun 24, 2019

Hi Stephen,
an excellent answer, thanks so much. I will try this method.
best
Zhang

@wdzth

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commented Jul 3, 2019

Hi Stephen,
I have not found the place to set the unspecific binding in GI tract. As your advice, I try it by defining a protein in the "individual" building block (expression, protein binding partners, reference concentration, location, intestinal mucosa, duodenum, upper and lower jejunium). and correpondingly defining the parameters koff kd, in the "compound" building block (ADME, distribution, specific binding, protein binding parterners). however it does not work. I wonder if anything wrong or ignored in setting.
could you please give some advices more detail? thank you.
best
Tianhong Zhang
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@tobiasK2001

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commented Jul 15, 2019

Dear Tianhong Zhang,

probably you found a better solution. However the apporach described by Stephan should work. However you should bring the sensitive parameters into a meaningfull range. E.g. the Reference concentration of the hypothetical binding partner should be in a similar range than your compound is dosed to have an effect. E.g. like this:
image

than you should see and effect like this
image
enterocyte lysosomes trapping simulation #346.zip

Please find the project attached. The only reason to chose Midazolam as compound was, to have it quick from the template database. No clue if it does Lysosomal trapping.

Hope this might help you.
Best Tobias

@StephanSchaller

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commented Jul 16, 2019

@wdzth sorry for not following-up. I missed your reply.

@tobiasK2001 thanks for picking up ;-)

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