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Open-Systems-Pharmacology / Fluvoxamine-Model

Whole-body PBPK model of fluvoxamine as CYP1A2 and CYP3A4 DDI perpetrator drug
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Source of inhibition constants for CYP1A2 not clear #3

Open AndreDlm opened 4 years ago

AndreDlm commented 4 years ago

I could not reconstruct where the following values of the inhibition constants for CYP1A2 (mixed inhibition) come from:

Annotation 2020-04-22 161833

@LMFuhr can you help out? Thanks!

LMFuhr commented 4 years ago

Hi @AndreDlm,

To describe the inhibition of CYP1A2 by fluvoxamine, the reported Ki value of 11 nmol/l (Karjalainen et al. 2008) was corrected for fluvoxamine binding in the in vitro test system as recommended by Yao et al. 2001.

The resulting Ki of 10 nmol/L was then used in the model.

You can find detailled information on the calculation of the Ki value in the Supplementary Material of @HannahBri 's publication (PBPK models for CYP1A2 DDI prediction):

Supplementary Material, Section 3.2

Feel free to contact us if you have any more questions.

Best regards, Laura

AndreDlm commented 4 years ago

Hi @LMFuhr and @HannahBri,

thanks for your fast feedback - I still have some questions, though :) It seems that the inhibitor constant of 11 nmol/L reported by Karjalainen 2008 was estimated from a competitive inhibition model, so that won't be readily transferable to a mixed-type inhibition model.

Yao 2001 on the other side fitted a mixed-type inhibition model to the data, but they did not report values for alpha or Ki,u.

Can you help out or does the model need a refinement/update? Thanks a lot!

Best regards, André