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IV and Oral doses for biliary processes- How to proceed with a good fit? #410

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PriKalra opened this issue Oct 30, 2019 · 11 comments
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@PriKalra
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@PriKalra PriKalra commented Oct 30, 2019

Dear all,

I have a compound, which seems to show biliary excretion as we see a second peak in the data for oral dose (species:Rats). Elimination is predominantly seen via urine and to a small extent via feces. In such a case, I simulated the IV dose with and without biliary excretion and there, the inclusion of biliary clearance improves the fit, but does not replicate the second peak of the biliary clearance. See below:
image

I do know from the data that the concentrations of the compound found in liver are low (after oral dose). What other parameters I could analyse and have a better understanding to the biliary processes?

When I proceed with this fit to simulate oral doses, the simulation fails to predict the plasma concentrations well.

image

Any ideas to test the model and improve the model fit would be appriciated as I have limited knowledge at tackling EHC.

Thanks
Pri

@sfrechen

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@sfrechen sfrechen commented Oct 30, 2019

If you believe your second peak really results from EHC, you may test inclusion of gallblader-empyting events (probably somewhat related tu teh administration of food). Just adding a biliary clearance in the model results in a constant biliary excretion from the liver into the bile system, i.e. partially into the gall blader, partially into teh duodenom. The fraction reaching the gallblader has to be emptied with such events, otherwise it will stay there.

@PriKalra

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@PriKalra PriKalra commented Oct 30, 2019

In all the studies, EHC has been indicated where, the most clearance happens in the Urine and not in Feces. Thank you for the explanation.
How do I do this in Rats where there is no gallbladder?
Further to this, I have some data on % excretion in Urine for the oral dose and there too, I am not able to replicate the scenario.

image

Also, is it correct to see the concentration in Duodenum lumen having the same trend as the % measured in Urine(see below)?
image

@PavelBal

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@PavelBal PavelBal commented Nov 5, 2019

It does not make any sense that the fraction excreted via urine decreases over time, and starts at almost 100%! There must be some misinterpretation of the data.

@PriKalra

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@PriKalra PriKalra commented Nov 5, 2019

The data shows that the fraction excreted is 77% at 5 hours, and then over the coming hours it decreases.

I implemented the measurement the way it is because it was in percentage. What would be a misinterpretation here?

@tobiasK2001

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@tobiasK2001 tobiasK2001 commented Nov 5, 2019

Ah, Ok (sorry for jumping in) in that case you should transform your fraction excreted data as cumulative data. As PK sim does. E.g. like after 5h 77%, after 12 h 77% +fraction excreted between 5 and 12 h. etc.
However, I cannot see a reason for linking urinary excretion data to EHC. In my eyes you need an experiment in bile duct cannulated rats to get an experimental proof here.

Hope this might help you.

Best, Tobias

@PriKalra

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@PriKalra PriKalra commented Nov 5, 2019

Thank you for the correction. I will do so. I was not linking it. It seemed strange to me that the graph looked similar to the data (which Imisinputted as pavel said).

Thank you.

@PriKalra

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@PriKalra PriKalra commented Nov 5, 2019

I also wanted to have your suggestions to know how I can improve the fit for the plasma (first question). How do I implement a process like the gallbladder emptying event in rats?

Thank you

@tobiasK2001

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@tobiasK2001 tobiasK2001 commented Nov 5, 2019

hmm, I am not sure if it is wise to implement gallbladder emptying for the rat, when it does not have a gallbladder. Did you ruled out any possible other reasons for the second peak?
PK-sim of course does not let you add a gallbladder emptying event for the rat given the reasons above. I am sure there are ways to add a gallbladder to a rat with MoBi. However, I would prefer to do a cheap trick first. Try creating a giant Mice with Bodyweight, organ volumes and liverbloodflow adapted to a rat. With that mice-rat chimera you might try to investigate the impact on gallbladder emptying further.

Hope that might help you.

Best, Tobias

@PriKalra

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@PriKalra PriKalra commented Nov 5, 2019

I see, no I have not ruled out any other possible reason for the second peak. I am not sure what else can allow this peak.

@RobinM92

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@RobinM92 RobinM92 commented Nov 6, 2019

@PriKalra

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@PriKalra PriKalra commented Nov 6, 2019

Hi Robin,

Thank you so much for this comment. Does enterogastric recirculation occur for acidic compounds too?

Best,
Priyata

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