Use of cytochrome P4503A4 intersystem extrapolation factors from three substrates in the estimation of fractional metabolism values for omeprazole

ISEF ParametersCLintfm
rCYPReactionISEF ValueCYP Abundance units of pmol/mg microsomal proteinrCYP CLint,u
(ยตL/min/pmol P450)
HLM CLint,sc,u (mL/min/kg)a
In Vitro
In Vivo
rCYP3A41โ€™-Hydroxymidazolam Formation0.2675.40.600.27b
Vardenafil Depletion0.291372.3584.10.63
Quinidine Depletion0.04412.80.21
rCYP2C19(S)-Mephenytoin 4โ€™-Hydroxylation0.50c147.8449.40.37-0.790.85d
  • aBinding values were scaled using the equation described in Austin et al. (2002), from values generated via equilibrium dialysis. Measured unbound fraction in microsomes for omeprazole was 0.90 at 0.71 mg/ml, which scaled to fu,mic of 0.98, 0.99, and 0.87 for heterologously expressed individual P4503A4, heterologously expressed individual P4502C19, and human liver microsome incubations, respectively.

  • bCalculated from clinical data reported in Bottiger, et al., 1997.

  • cCytochrome P450C19 intersystem extrapolation factor determined from mephenytoin 4โ€™-hydroxylase activity (internal data on file, Pfizer, Inc.) This intersystem extrapolation factor has been used successfully for other CYP2C19 cleared drugs.

  • dMedian fractional metabolism value calculated from fifty clinical studies in which omeprazole was dosed to cytochrome P450C19 extensive and poor metabolizers, obtained from the University of Washington Drug Interaction Database.