How to create an enzyme process for bacterial β-glucuronidase in intestinal lumen

[Yu1972]

Dear OSP community,
I’m developing a PBPK model of rat for a compound & its major metabolite involving EHC process. The parent compound is administered by IV and metabolized via UGT enzymes in liver. The glucuronide is then excreted from bile into intestinal lumen and is deconjugated by bacterial β-glucuronidase in cecum and colon before the parent compound is re-absorbed mostly from colon.
I created bacterial β-glucuronidase in intestinal lumen for the glucuronide using first-order process. The parameter (total activity, nmol/min) is from the data below. However, with and without this β-glucuronidase, the plasma concentration curves of the parent and glucuronide doesn’t make any difference.
My questiones are:

1. How to create bacterial β-glucuronidase right?
2. How does PK-SIM scale it when the enzyme is from intestinal lumen content rather than tissue?
   Thanks in advance
   Yu
   
   
   

[Yu1972]

Is there any suggestion here? Highly appreciate your support!

[OneWay289]

Hi Yu1972,

Did you ever find a solution to your problem? I am working on a similar problem although it is probably not as complicated. The compound I'm dealing with is hydrolyzed in the colon by a bacterial esterase. I have the needed kinetic information but don't know how to enter it. I tried the procedure that tobiask2001 recommended to someone else for a different problem (see discussion #1433) on January 13, 2003. He recommended simply entering kcat for the Speific Clearance for Total Hepatic Clearance. It worked OK for me although mine is a different application. However, I have kinetics for the wild type and two mutants. I entered the kcat for wild type, but then when I changed to the kcat for one of the mutants, the elimination did not change. I'm not sure why.

If you figure out how to resolve your problem I would be interested in knowing what you did and I would be glad to share my solution, if I find one.

Thanks!

[PavelBal]

Did you implement biliary clearance of the metabolite, or active transport of the metabolite from liver into gut?

[OneWay289]

Thanks very much for your reply. I am a student and a new PK-Sim user. I have encountered several problems that I have been struggling to resolve. I am taking the ESQlabs training courses which are quite helpful. I am working with a compound in a natural product extract, not a drug, so much of the information normally available for a drug (such as an IV PK study) is not available. After the compound is hydrolyzed by bacterial esterases, it is extensively metabolized by mammalian enzymes. I don't know how to implement biliary clearance. Can you please explain this? After hydrolysis, the metabolites are formed in the colon wall or liver, so I think transport would be from the gut to the liver rather than the other way. Since there is no human IV study, I'm trying to complete interspecies scaling too, but my progress with this has been slow so I decided to work on human metabolism and come back to that later. Thanks again!

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On Mon, Mar 10, 2025 at 10:44 AM Pavel Balazki ***@***.***> wrote: Did you implement biliary clearance of the metabolite, or active transport of the metabolite from liver into gut? — Reply to this email directly, view it on GitHub <#1904 (comment)>, or unsubscribe <https://github.com/notifications/unsubscribe-auth/BCTJMETXZMELDTAGNSER4GL2TWXPHAVCNFSM6AAAAABV3FZCAGVHI2DSMVQWIX3LMV43URDJONRXK43TNFXW4Q3PNVWWK3TUHMYTENBVGEYTAMI> . You are receiving this because you commented.Message ID: <Open-Systems-Pharmacology/Forum/repo-discussions/1904/comments/12451101@ github.com>