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Open-Systems-Pharmacology / OSP-PBPK-Model-Library

Library of released PBPK substance models and evaluation reports
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Questions about expressed proteins #62

Open PavelBal opened 2 years ago

PavelBal commented 2 years ago

In the published models (especially those using the "European (P-gp modified, CYP3A4 36 h)" individual), I found some differences in the expression profiles from the values stored in the database.

Should I always use these values in new projects if I want to combine the models with the published models (e.g. for DDI)? How do I justify these values?

@sfrechen

PavelBal commented 2 years ago
PavelBal commented 2 years ago

UGT2B7: Expression profile from EST and not RT-PCR is used; reference concentration overwritten.

sfrechen commented 2 years ago
  • CYP3A4 half-life changed from 37 to 36 hours

36 is the correct value from the paper that PK-Sim refers to. The database contains an error here.

  • UGT1A4 reference concentration changed from 1 to 2.32 µmol/l
  • Expression of UGT1A4 is completely different from that coming from the DB. What is UGT1A4? Does it correspond to any data base entry at all, or is it manually entered?

Please see evaluation report of midazolam.

  • ATP1A2 reference concentration changed from 1 to 0.39 µmol/l

Please refer to Hanke et al. 2018.

  • GABRG2 reference concentration changed from 1 to 1.04 µmol/l, and is only expressed in Brain as opposed to data base

Please see evaluation report of midazolam.

  • What is the source of P-gp expression? I cannot find a corresponding entry in the data base (Array/EST/RT-PCR). also the reference concentration?

Please refer to Hanke et al. 2018. The P-gp expressionis in principle adopted from RT-PCR and was slightly modified using the model substrate digoxin.

  • OATP1B1 is changed from Efflux to Influx???

OATP1B1 is an influx. Is it really defined per default as efflux?

  • AADAC: Relative expression in blood cells added, by default is not present

The profile represents exactly the RT-PCR profile with extremely little expression in blood cells (3.9E-05)

  • Where does the ontogeny for p-gp come from?

@Incei : can you help?

UGT2B7: Expression profile from EST and not RT-PCR is used; reference concentration overwritten.

Cannot reproduce. I see for dapagliflozin that RT-PCR is used. Wrt. reference concentration please refer to evaulation report of dapagliflozin.

Should I always use these values in new projects if I want to combine the models with the published models (e.g. for DDI)? How do I justify these values?

Well, once we have the new feature with the expression building block, we should see for harmonied documentation at ONE place...

PavelBal commented 2 years ago

@sfrechen Thank you, that makes things clear.

OATP1B1 is an influx. Is it really defined per default as efflux?

Yes, it is efflux by default, but actually the DB does not provide any information about the direction (efflux is therefore just a "default" placeholder). Version 9 showed a warning about it, V10 does not: https://github.com/Open-Systems-Pharmacology/PK-Sim/issues/2034

The profile represents exactly the RT-PCR profile with extremely little expression in blood cells (3.9E-05)

Seems to be a bug in V10: https://github.com/Open-Systems-Pharmacology/PK-Sim/issues/2039

Cannot reproduce. I see for dapagliflozin that RT-PCR is used. Wrt. reference concentration please refer to evaulation report of dapagliflozin.

The carbamazepine models seems to use different expression: https://github.com/Open-Systems-Pharmacology/Carbamazepine-Model/issues/1

sfrechen commented 2 years ago

The carbamazepine models seems to use different expression: Open-Systems-Pharmacology/Carbamazepine-Model#1

The model is not yet part of the library. We are currently rebuilding the model. But thanks for spotting.

prvmalik commented 2 years ago

Along these lines @sfrechen could you share how the correction factors from v9.1 to v10 were calculated for ATP1A2 concentration, OATP1B1 vmax, and GARBG2 concentration. I must perform similar calculations to update models.

When using rifampicin model in V10 yes the user must know to add in the blood cell relative expression on their own.

Yuri05 commented 2 years ago

@prvmalik

When using rifampicin model in V10 yes the user must know to add in the blood cell relative expression on their own.

Why that? Can you explain?

prvmalik commented 2 years ago

@Yuri05 when loading AADAC from the database, red blood cell expression does not populate in v10. It was in the original model. So when using the model for your own purposes the user has to add in the 3.9e-05 in the blood cells and vasc Endo for sameness. You can't import 'individual' building blocks as templates in the same way that you can do compounds, formulations, admin protocols, etc. But having the European DDI individual as a template would solve this a bit.

Yuri05 commented 2 years ago

@prvmalik Ok, I see. You are right, that's a bug. It's what's being discussed in https://github.com/Open-Systems-Pharmacology/PK-Sim/issues/2039

sfrechen commented 2 years ago

Along these lines @sfrechen could you share how the correction factors from v9.1 to v10 were calculated for ATP1A2 concentration, OATP1B1 vmax, and GARBG2 concentration. I must perform similar calculations to update models.

When using rifampicin model in V10 yes the user must know to add in the blood cell relative expression on their own.

@prvmalik Yes, I will do. I have a matlab script for that. I will create a github repo (first on my personal github) and share it later.

sfrechen commented 2 years ago

As promised @prvmalik @Yuri05 @PavelBal Please find the scripts and a small workflow instruction here:

https://github.com/sfrechen/Migration-PK-Sim-9-to-10

PavelBal commented 2 years ago

I see that for some enzymes, expression value for "Cecum" has been manually added? By default, it is always 0 when coming from the data base.

1) Why is it not extended for ALL enzymes (e.g. fur UGT2B7 but not for CYP3A4)

2) For UGT2B7, also the expression value of "Rectum" is set. I think this is the only enzyme where it has been done.

@sfrechen Can you comment? Should it not be unified?

PavelBal commented 2 years ago
PavelBal commented 7 months ago

@sfrechen @Yuri05 Could you provide some information about the reference concentration of ABCG2 (BCRP)? I could not find a project where this transporter is actually used, but it is present in the dapagliflozin project with a reference concentration of 9.2 nmol/l, value origin is "Tucker et al.".

In the rosuvastatin model https://github.com/Open-Systems-Pharmacology/Rosuvastatin-Model by @NinaHanke , a value of 0.025 µmol/l, value origing is unknown. We are trying to understand where the different values come from and which value should be used when combining models for DDI predictions.

NinaHanke commented 7 months ago

Dear @PavelBal the =0.025 µM for BCRP were calculated from: transporter amount per mg membrane protein * 37.0 mg human membrane protein per g liver

[Prasad B, Evers R, Gupta A, Hop CECA, Salphati L, Shukla S, Ambudkar SV, Unadkat JD (2014) Interindividual variability in hepatic organic anion-transporting polypeptides and PGlycoprotein (ABCB1) protein expression: Quantification by liquid chromatography tandem mass spectroscopy and influence of genotype, age, and sex. Drug Metabolism and Disposition 42(1):78–88] [Prasad B, Lai Y, Lin Y, Unadkat JD (2013) Interindividual variability in the hepatic expression of the human breast cancer resistance protein (BCRP/ABCG2): effect of age, sex, and genotype. Journal of pharmaceutical sciences 102(3):787–93]

See Rosu-paper supplement page 59 "7 System-dependent parameters". If we used a different ref conc before (can't remember) we scaled the kcat of the respective model to the new ref conc, so that the product of ref conc * kcat is the same.

PavelBal commented 7 months ago

@NinaHanke Thank you!