Implementation of active transporters

[pdlj671]

Hi all,

I am currently working on incorporating an active transport in a pregnancy model. In particular, I was looking at incorporate an efflux transporter, P-gp, on the apical side of the placenta. I am still new to MoBi so I was trying to get an understanding if it was possible do the following methods in adding the transporter.

I used this approach to develop the pregnancy model https://github.com/Open-Systems-Pharmacology/Pregnancy-Models/tree/pregnancy-modules

First approach

I am not too sure why this works as I am able to plot process rates due to transporters. First, I include transport proteins in the base PBPK model and wherever this protein is expressed the molecule will be uptaken by the transporter. Then, I send the base PBPK model to MoBi.

Now, since I wanted to extend this to the placenta I cloned the based PBPK model (call it PBPK model w/ placenta transporter). I added another transport within the transporter protein called "Uptake into placenta". I added clearance rates and input a formula as well.

Lastly, I just followed the above tutorial and extended the model.

It would be

Base PBPK Model -> Cloned base PBPK Model (w/ transporter equation for uptake into fetal part of placenta) -> maternal structure -> simple fetal structure

My understanding is that the active transporter will be extended and used in pregnancy, but only given that the transporter protein exists.

Second Approach

My second approach was to use the passive transports building block within maternal structure module. Since I am not too worried about the P-gp uptake anywhere else other than the placenta at the moment, I thought this would be a decent work around. I am able to obtain the process rate to show that it is working.

Third Approach

I tried to add the P-gp transport manually following the documentation found here.

That is, I created PGP along with the parameters and paths to move from

PlacentaFetal|Intracellular -> PlacentaMaternal|Plasma

This didn't seem to work and I'm not too sure why. I thought it was mainly since there was no existing transport protein or I am not understanding the modularization concept correctly.

I guess my questions are is there a way to do the third approach? Why does approach 1 work with the existing transport protein versus not having one in the base PBPK model?

Also, would adding a separate module that contains that transport be doable? That is,

PBPK Base Model -> Maternal Structure -> Fetal Structure

with the transporter module being incorporated within.

If the PK-Sim or MoBi files are needed, then I would be able to provide them. Thank you!

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[pdlj671]

Hi all,

I managed to figure it out. I'll write out what I did in case someone might find it useful. The thing I was missing was an initial conditions building block within my extended module.

Step 1:

Send base PBPK model to MoBi and save molecule as a .pkml file.

Step 2:

Create extended module with molecule and IC building blocks.

Step 3:

Create transporter molecule within the molecule building block (Pgp, BCRP, etc.). Then create transport. I followed the steps here.

Step 4:

Under initial conditions building blocks in your extended module, extend and select the molecules in your extended model. Note: spatial structure that I used was the maternal structure if working on pregnancy.

Step 5:

Tick the create process rate parameter and plot process rate parameter boxes to see if it works.