How can I assigne the contribution enzyme

[moulirc]

The drug is metabolized by multiple enzymes. How I can assign enzymes for a drug metabolism.

60% CYP2D6, 10% CYP1A2, 5% CYP2C9, 5% CYP2E1, and 20% UGT Please advise

mouli

[prvmalik]

Model total hepatic clearance (mL/min) using 1 metabolizing enzyme. Manually adjust the intrinsic clearance value to match the total hepatic clearance on the profile.

Calculate a composite for total hepatic intrinsic clearance (umol*mL/min) by: Comp = refC(1) x CLint(1) Where CLint(1) is the intrinsic clearance value required to match total hepatic clearance on the PK profile and where refC(1) is the reference concentration of the 1 enzyme used

Re-Calculate intrinsic clearance for each enzyme (i) by: CLint(i) = Comp x RelCon(i) / RefC(i) Where RelCon(i) is the relative contribution (%) of that enzyme to hepatic clearance and where RefC(i) is the reference concentration of that enzyme

[moulirc]

Hi Malik,

thanks for your guidance.

kind regards mouli

[DanielMoj]

moulirc,

in case you do not want to use the total hepatic clearance but e.g. michaelis menten kinetics and tissue-specific distribution of the enzymes using the gene expression database you could also do the following:

1. Implement the above mentioned enzymes with literature vmax and km values.
2. Go to MoBi and build an observer that sums up all intracellular amounts for each metabolite formed by one of the enyzmes. (As long as you do not try to model the metabolites with logP values etc., the formed metabolites will stay in the intracellular compartments.) Divide the sumed up amounts by the administered dose and you get the actual % contribution of each enzyme.
3. To assign % contributions you can then import the above mentioned % values. Link the generated observers to the imported % values and fit e.g. the Vmax values or reference concentrations of the enzymes to match the simulated with the observed % values.

Best Daniel