Grzegorzewski2022 - PBPK model of dextromethorphan

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Physiologically based pharmacokinetic (PBPK) modeling of the role of CYP2D6 polymorphism for metabolic phenotyping with dextromethorphan
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  • Physiologically based pharmacokinetic (PBPK) modeling of the role of CYP2D6 polymorphism for metabolic phenotyping with dextromethorphan.
  • Grzegorzewski Jan, Brandhorst J, Matthias König
  • Frontiers in pharmacology 2022 , Volume 13 , pages: 1029073 , PubMed ID: 36353484
  • Institute for Theoretical Biology, Institute of Biology, Humboldt University, Berlin, Germany.
  • The cytochrome P450 2D6 (CYP2D6) is a key xenobiotic-metabolizing enzyme involved in the clearance of many drugs. Genetic polymorphisms in CYP2D6 contribute to the large inter-individual variability in drug metabolism and could affect metabolic phenotyping of CYP2D6 probe substances such as dextromethorphan (DXM). To study this question, we (i) established an extensive pharmacokinetics dataset for DXM; and (ii) developed and validated a physiologically based pharmacokinetic (PBPK) model of DXM and its metabolites dextrorphan (DXO) and dextrorphan O-glucuronide (DXO-Glu) based on the data. Drug-gene interactions (DGI) were introduced by accounting for changes in CYP2D6 enzyme kinetics depending on activity score (AS), which in combination with AS for individual polymorphisms allowed us to model CYP2D6 gene variants. Variability in CYP3A4 and CYP2D6 activity was modeled based on in vitro data from human liver microsomes. Model predictions are in very good agreement with pharmacokinetics data for CYP2D6 polymorphisms, CYP2D6 activity as described by the AS system, and CYP2D6 metabolic phenotypes (UM, EM, IM, PM). The model was applied to investigate the genotype-phenotype association and the role of CYP2D6 polymorphisms for metabolic phenotyping using the urinary cumulative metabolic ratio (UCMR), DXM/(DXO + DXO-Glu). The effect of parameters on UCMR was studied via sensitivity analysis. Model predictions indicate very good robustness against the intervention protocol (i.e. application form, dosing amount, dissolution rate, and sampling time) and good robustness against physiological variation. The model is capable of estimating the UCMR dispersion within and across populations depending on activity scores. Moreover, the distribution of UCMR and the risk of genotype-phenotype mismatch could be estimated for populations with known CYP2D6 genotype frequencies. The model can be applied for individual prediction of UCMR and metabolic phenotype based on CYP2D6 genotype. Both, model and database are freely available for reuse.
Submitter of the first revision: Matthias König
Submitter of this revision: Matthias König
Modellers: Matthias König

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Model files

dextromethorphan_body_flat.xml Dextromethorphan PBPK model (SBML) 543.06 KB Preview | Download

Additional files

cyp2d6.xml Dextromethorphan CYP2D6 comp model (SBML) 121.64 KB Preview | Download
dextromethorphan_body.xml Dextromethorphan PBPK comp model (SBML) 423.37 KB Preview | Download
dextromethorphan_intestine.xml Dextromethorphan intestine comp model (SBML) 27.60 KB Preview | Download
dextromethorphan_kidney.xml Dextromethorphan kidney comp model (SBML) 25.61 KB Preview | Download
dextromethorphan_liver.xml Dextromethorphan liver comp model (SBML) 147.14 KB Preview | Download

  • Model originally submitted by : Matthias König
  • Submitted: Jan 9, 2023 1:09:58 PM
  • Last Modified: Jan 9, 2023 1:09:58 PM
  • Version: 1 public model Download this version
    • Submitted on: Jan 9, 2023 1:09:58 PM
    • Submitted by: Matthias König
    • With comment: Import of Grzegorzewski2022 - PBPK model of dextromethorphan