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Comparison CYP2C19, 2C9, 2D6 and CYP3A4 intestinal CYP abundance in PK-sim to other PBPK Models #204

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tobiasK2001 opened this Issue Aug 1, 2018 · 0 comments

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tobiasK2001 commented Aug 1, 2018

Dear all,
here is a more general question regarding CYP abundance in PK-sim.
Having a look at the total intestinal CYP abundance for 2C19 it seems to be quite high. Actually 2C19 expression seems to be in the range of CYP3A4 abundance and this withspread some literature (PMID: 16467132). Comparing other CYP enzyme expression to other literature (Olivares Morales et al. PMID: 27631556, TableI) they seem to be also somewhat different.
Here PK-Sim CYP abundance was calculated using RT-PCR expression database. The simulation was exported from PK-sim to MobI and the amount of CYP for each intestinal segment was displayed. To Compare to Olivares Morales et al. gut model, the amount for lower and upper Jejunum or Illeum were added to total Illeum or Jejunum, respectively. I hope this is the right way. Please let me know if not. Interstingly CYP3A4 total expression seems to be quite similar in PK-sim and Olivares Morales et al.
grafik

I wonder if the differences for CYP2C19, 2C9, 2D6 intestinal and liver expression may cause problems for Identifying parameters for CYP-metabolism and Intestinal permeability for in PK-Sim models for compounds metabolised mainly by this enzyme. That maybe in contrast to CYP3A4 substrates. Or may this expression differences interfere with DDI prediction for CYP2C19, 2C9, 2D6 substrates? Does anybody had similar experiance? Did anyone had tried to alternate CYP2C19, 2C9, and 2D6 abundance to get improved results? Or did it had no impact at all?

Thanks in advance for sharing your experiance!

Kind regards, Tobias

@Yuri05 Yuri05 added the question label Aug 30, 2018

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