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

[PriKalra]

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:

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.

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]

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]

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.

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

[PavelBal]

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]

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]

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]

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]

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]

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]

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]

Hello Priyata,

Enterohepatic recirculation seems indeed a bit difficult as rats don't have a galbladder. Another possibility might be enterogastric recirculation (is it a basic compound?), which is much less described but still can be relevant, especially for alkaline compounds (e.g. https://www.ncbi.nlm.nih.gov/pubmed/8237395 and more recent https://link.springer.com/article/10.1007%2Fs10928-014-9371-3).

Good luck! Robin

Dr. ir. Robin Michelet Post-doctoral researcher

Freie Universitaet Berlin Institute of Pharmacy Dept. of Clinical Pharmacy & Biochemistry Kelchstr. 31 12169 Berlin Germany Phone: + 49 30 838 50659 Fax: + 49 30 838 4 50656 Email: robin.michelet@fu-berlin.de www.clinical-pharmacy.eu

On 06-11-19 12:11 AM, Priyata wrote:

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.

— You are receiving this because you are subscribed to this thread. Reply to this email directly, view it on GitHub https://github.com/Open-Systems-Pharmacology/Forum/issues/410?email_source=notifications&email_token=AHKFXQZ4UMV6M3FYFUVYL7TQSH4RLA5CNFSM4JGVNVP2YY3PNVWWK3TUL52HS4DFVREXG43VMVBW63LNMVXHJKTDN5WW2ZLOORPWSZGOEDEVKRY#issuecomment-550065479, or unsubscribe https://github.com/notifications/unsubscribe-auth/AHKFXQ73HKCWNXBIG672PZLQSH4RLANCNFSM4JGVNVPQ.

[PriKalra]

Hi Robin,

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

Best, Priyata

[Yuri05]

@PriKalra Closing. Please reopen if there are still any questions.