Footnotes

• Abbreviations used are::

  HPLC

  high-performance liquid chromatography

  LC-MS/MS

  liquid chromatography-tandem mass spectrometry

  CL_{int, in vitro}

  in vitro intrinsic clearance observed when test compounds were metabolized by human hepatocytes suspended in human serum

  D

  cell density of hepatocytes suspended in serum

  T

  incubation time

  R

  ratio of intact drug concentration after incubation to that at time 0

  SF₇₀₊₇₃

  scaling factor calculated from CL_{int, in vitro, 70+73}/CL_{H, int, in vivo} for the pooled hepatocyte preparation of lot 70 and 73

  CL_{H, int, in vitro, 70+73}

  hepatic intrinsic clearance calculated from in vitro data using the pooled hepatocyte preparation of lot 70 and 73

  CL_{int, in vitro, 70+73}

  in vitro intrinsic clearance observed when test compounds were metabolized in the pooled hepatocyte preparation of lot 70 and 73 suspended in human serum

  F_H

  hepatic availability

  CL_{H, predicted, 70+73}

  predicted hepatic clearance from CL_{int, in vitro, 70+73} and average SF₇₀₊₇₃

  Q_H

  hepatic blood flow rate

  R_B

  blood-to-plasma concentration ratio

  D_N

  dispersion number

  CL_{P, in vivo}

  in vivo plasma clearance

  F_{PO, in vivo}

  oral bioavailability in humans

  CL_{H, int, in vivo}

  hepatic intrinsic clearance calculated from F_{PO, in vivo}by the dispersion model (using the Goal Seek method attached to Microsoft Excel)

  SF_mean

  mean of scaling factor calculated from CL_{int, in vitro, mean}/CL_{H, int, in vivo} for 10 individual lots

  average SF_mean

  average value of SF_mean for seven standard compounds

  F_{H, predicted, 70+73}

  predicted hepatic availability from CL_{int, in vitro, 70+73} and average SF₇₀₊₇₃

  SF_biol

  biologically based scaling factor of hepatocellularity (3.1×10⁹ cells/kg)

  average SF₇₀₊₇₃

  average value of SF₇₀₊₇₃ for seven standard compounds

• • Received December 13, 2001.
  • Accepted April 24, 2002.