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Competitive inhibition of Hill kinetic active transport not working #351

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NinaHanke opened this issue Jun 24, 2019 · 4 comments

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@NinaHanke
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commented Jun 24, 2019

Dear masters of PK-Sim and MoBi,

I tried to add a competitive inhibition to a transporter with a Hill kinetic (Hill coefficient = 3.0).
Nothing happened... (if I change transporter Km, -kcat or -concentration, I see the effect).

When I export to MoBi, there is no Km_app, although I have the competitive inhibition configured in PK-Sim, before exporting to MoBi (see picture on the left).
When I change this transporter to a normal Michaelis-Menten active transport with competitive inhibition, everything is fine in my MoBi file, (see picture on the right).

grafik

Trying to add Km_app in MoBi did not work, because he did not like the paths I added for K_water1 and KcI1, even when I copied them from the working MoBi file (SOURCE|Perpetrator|Partition coefficient (water/container) and SOURCE|Perpetrator|Concentration) to build the
Km interaction factor = 1 + K_water1*Ic1/KcI1.

Is this a known problem, or did I make a mistake?

Please help :)
Cheers,
Nina

@Yuri05

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commented Jun 26, 2019

Is this a known problem, or did I make a mistake?

It's a feature 😄
Combination {DDI+Hill kinetics} is deactivated by design.
Simply due to the fact that we did not invest time into developing the common DDI formulas for the Hill kinetics.
Everybody who could invest time into developing those formulas for Hill is welcome 😉

S. also: Open-Systems-Pharmacology/PK-Sim#1283

@sfrechen @TWendl FYI

@NinaHanke

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commented Jun 26, 2019

Ok, many thanks Juri!!!!!

Then I will try a work-around via Km.
And next time maybe resist the urge to implement cooperativity 😕

@msevestre msevestre closed this Jun 26, 2019

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commented Jul 1, 2019

@NinaHanke
For which transporter is cooperativity described?
How would you like to implement competitive inhibition in such a case? Which model do you want to apply?

@sfrechen sfrechen reopened this Jul 1, 2019

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commented Jul 1, 2019

Its for PMAT, a transporter involved in metformin absorption.
https://www.ncbi.nlm.nih.gov/pubmed/17600084

I wanted to see how the metformin DDI looks like, if I add competitive inhibition of PMAT (no experimental data available, just hypothesis testing).

Not sure how to build it in though, as I could not find any formulas in literature, yet.
I would probably just change the Km, as always with competitive inhibition, as a first guess.

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