Evaluating a physiologically-based pharmacokinetic model for prediction of omeprazole clearance and assessing ethnic sensitivity in CYP2C19 metabolic pathway

Sheng Feng, Yumi Cleary, Neil Parrott, Pei Hu, Cornelia Weber, Yongqing Wang, Ophelia Q. P. Yin, Jun Shi

J. Shi is the correspondence author.

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Summary of Input Parameters for Omeprazole PBPK Model (default values in SimCYP).

Parameters / Omeprazole
Physicochemical properties
Molecular weight (g/mol) / 345.4
log P / 2.230
Compound Type / Ampholyte
pKa 1 (acidic) / 8.700
pKa 2 (basic) / 4.400
Blood/plasma ratio / 0.590
Haematocrit (%) / 45
Fraction unbound / 0.043
Absorption
Absorption type / ADAM
Peff, man (×10–4cm/s) / 3.245
fuGut / 1
Formulation / Enteric-Coated Granules
Triggering pH / 4.9
Distribution
Distribution model / Minimal PBPK Model
Vss (L/kg) / 0.23 (Caucasians), 0.249 (Chinese), 0.219(Japanese)
Elimination
Enzymes / CYP2C19; CYP3A4
CLint (µL/min/mg - microsomal protein) / 264.17 (CYP2C19),39.47 (3A4)
fu mic / 1.00
CLRenal (L/h) / 0.037

ADAM: Advanced dissolution, absorption and metabolism model, fuGut: fraction unbound in the enterocytes, Vss:Volume of distribution at steady state, was the mean of parameter estimates based on the individual concentration [1] for Chinese and Vssfor Caucasians [2] and Japanese [3] were the values reported in the literature. They were modified from default values.Clint:Intrinsic clearance, fu mic: Fraction of drug unbound in an in-vitro microsomal preparation, CLRenal: Renal clearance.

REFERENCES

  1. Wang Y, Zhang H, Meng L, Wang M, Yuan H, Ou N, Zhang H, Li Z, Shi R. Influence of CYP2C19 on the relationship between pharmacokinetics and intragastric pH of omeprazole administered by successive intravenous infusions in Chinese healthy volunteers. Eur J Clin Pharmacol. 2010; 66:563-9.
  2. Regårdh CG, Andersson T, Lagerström PO, Lundborg P, Skånberg I. The pharmacokinetics of omeprazole in humans--a study of single intravenous and oral doses. Ther Drug Monit. 1990; 12:163-72.
  3. Ishizawa Y, Yasui-Furukori N, Takahata T, Sasaki M, Tateishi T. The effect of aging on the relationship between the cytochrome P450 2C19 genotype and omeprazole pharmacokinetics. Clin Pharmacokinet. 2005; 44:1179-89.