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Increased Cmax and AUCs of metabolite by enzyme inhibitor

metabolite inhibitor

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#1 LLLi

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Posted 02 November 2016 - 02:03 AM

Hi All,

 

I have a question that is not related to the WinNonlin software usage. But I still posted here and hope somebody can help me.

 

I am investigating the drug-drug interaction of a CYP3A4 inhibitor and compound A. Compound A is primarily metabolized by CYP3A4 inhibitor. One of the metabolites of A is M1. The metabolism of A is not very clear yet.

 

My results show that the inhibitor could increase the Cmax and AUCs of A. Surprisingly, the inhibitor could also increase the the Cmax and AUCs of M1 and slightly increase the ratio of M1 to A (Cmax and AUCs ratio). I am very confused by these results. What is the possible reasons that the inhibitor increase the exposure of both parent drug and its metabolites?

 

Thank you! Any input is appreciated!

 

LLLi


Edited by LLLi, 02 November 2016 - 02:05 AM.


#2 Nathan Teuscher

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Posted 02 November 2016 - 02:46 AM

What is the metabolic pathway for M1? If it is further metabolized by CYP3A4, then the phenomenon you observed could occur.

 

Nathan



#3 LLLi

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Posted 04 November 2016 - 02:02 PM

Dear Nathan,

 

Thank you for your reply!

 

Unfortunately, we don't know the metabolism of M1 right now. Besides the reason that you mentioned, is there any other things that can cause this phenomenon?

 

Furthermore, would you please provied some infomration on how to the measure the systemic clearance (CLsys) of metabolites? I found an abstract in which the authors compared the CLsys of metabolite under normal and CYP inhibited conditions. 

 

Thank you!

 

LLLi



#4 PJLARGER

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Posted 06 November 2016 - 08:27 PM

Dear LLLi,

 

Like Nathan I think the most likely explanation is that M1 is metabolized by CYP3A4.

If the inhibitor dose used leads to about complete inhibition of CYP3A4, it is likely that A is metabolized to M1 mainly by another isoform. Note that some phenotyping experiments tend to identify 3A4 as the main mechanism when other isoforms are also relevant.

Could you please provide the reference of the paper evaluating CLsys of metabolites.

 

Patrice



#5 LLLi

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Posted 07 November 2016 - 02:31 PM

Hi Patrice,

 

Thank you for your reply.

 

I only found an abstract which mentioned the measurement CLsys of metabolites. This is why I asked here if anyone knows more about the measurement. Please see the abstract attached. 

 

LLLi

 







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