Problem of sequential metabolism PBPK model

[mmalsmadi]

Hello

I am trying to simulate the PK of the parent compound (methadone R and S stereoisomers) and their common metabolite (EDDP) after IV-bolus and oral administration

The parent compound simulate fine, but the metabolite (EDDP) doesn't show even previous work showed possible similar simulation using PK-Sim
https://pubmed.ncbi.nlm.nih.gov/35491971/

Any thoughts on what causes this issue

P.S. The PK-Sim simulation file is attached here.
Methadone & EDDP.zip

Thanks

[Yuri05]

seems something is missing in your model.
E.g. looking at the EDDP venous blood concentration in the 1st simulation: it's const zero in your simulation, while in the paper it's apparently not.

[Yuri05]

All enzymes in your project have relative expressions=0 everywhere, that's why