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Enterohepatic recycling of parent drug- conjugated metabolite #247

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mmalsmadi opened this Issue Nov 13, 2018 · 4 comments

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@mmalsmadi
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mmalsmadi commented Nov 13, 2018

Hello,

I need help in modifying a PBPK model in MoBi in order to include a step of hydrolysis of conjugated metabolite via gut flora glocurinidase enzymes to release the parent compound and its subsequent reabsorption in the lower small intestine and large intestine
I set a new reaction
image

I then added a formula and defined the value of 1st order parameter (k_Glocurinidase)
image

Now the MPAG is hydrolyzed to MPA, as shown by increased amount of MPA in feces,
The problem I didn't get the MPA to be reabsorbed and the plasma concentration time profiles of MPA and MPAG were not modified (i.e. MPA levels were supposed to increase by this process)

My questions are;

  1. what do I need to set additionally to get the MPA to be absorbed?
  2. How can I confine this to the lumen of the lower small intestine and large intestine only and exclude the stomach, dudenum, and jejunum?
  3. Could happen that there is an alternative built-in method in Pk-Sim that I am missing?

P.S.1. I set the following tags for the container criteria
image

P.S.2. I can't locate the paremter I am using (k_Glucuronidase) in the list of parameters start value

please help

Thanks
Motasem

@PavelBal

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PavelBal commented Nov 19, 2018

what do I need to set additionally to get the MPA to be absorbed?

In theory, nothing. MPA should be reabsorped based on its properties (lipophilicity, moleculat weight) and additional processes you defined (active transports, if applicable). Did you check whether MPA is actually produced in the intestine? I.e., plot the amounts of MPA in intestinal lumen?

How can I confine this to the lumen of the lower small intestine and large intestine only and exclude the stomach, dudenum, and jejunum?

The container criteria look good.

I can't locate the paremter I am using (k_Glucuronidase) in the list of parameters start value

By default, Parameter Start Values (PSB) building blocks do not include (global) parameters of reactions. However, you can create a corresponding entry by clicking on "New Parameter Start Value" in the ribbon bar and entering the name ("k_Glucuronidase") and the Path Element 0 ("LumenGlucuronidase") manually. The entry will be marked as "Source not defined" (blue background), but the value will be used in simulations.

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mmalsmadi commented Feb 20, 2019

Thank you for the help,
another thing, the fraction absorbed is calculated by PK-Sim to be 1.14 (i.e. >1)
Is this true or is there something wrong with this value being >1?

@Aedginto

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Aedginto commented Feb 20, 2019

If you have enterohepatic circulation, the fraction absorbed to the portal vein can be greater than one since the amount moving from gut lumen to portal vein can exceed total dose (e.g. if fabs is usually 1 in the absence of EHC such that there is no solubility or permeability limitation to uptake, then any additional amount delivered to gut by bile and ultimately being absorbed to portal will increase the amount moving from lumen to portal to a value greater than the dose).

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mmalsmadi commented Feb 26, 2019

Thank you again,

another thing, I am trying to model saliva level and the PBPK model predicts that the saliva levels are equal to the unbound plasma concentrations of the drug, is this always the case? Why?

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