Table 2

Comparison of CL H in vitro and in vivo

SpeciesParameterStereoisomer
SSSRRSRR
KK mice
In vitro CL H(ml/min/kg)2-a 14.57.7822.434.5
In vivo CL H(ml/min/kg)2-b 16.8 ± 1.3 29.3 ± 3.7 24.0 ± 2.0 42.1 ± 8.2 
In vitro/in vivo 2-c CL H 0.860.270.930.82
ddY mice
In vitro CL H(ml/min/kg)2-d 15.3
CL H,Sulf. (ml/min/kg)2-e 0.403
CL H,Glu. (ml/min/kg)2-e 14.9
In vivo CL tot(ml/min/kg)20.5
CL H,Sulf.(ml/min/kg)2-f 0.0765
CL H,Glu.(ml/min/kg)2-f 13.0
In vitro/in vivo 2-c CL H 2-g 0.75
CL H,Sulf. 5.3
CL H,Glu. 1.1
Rats
In vitro CL H (ml/min/kg)2-h 22.9
CL H,Sulf. (ml/min/kg)2-e 21.7
CL H,Glu. (ml/min/kg)2-e 1.17
In vivo CL tot(ml/min/kg)31.0  ± 1.42-i
CL H,Sulf. (ml/min/kg)2-f 21.1
CL H,Glu. (ml/min/kg)2-f 3.60
In vitro/in vivo 2-c CL H 2-g 0.74
CL H,Sulf. 1.0
CL H,Glu. 0.33
  • 2-a CL H based on dispersion model was calculated from equations 5 and 6 with Q H = 90 ml/min/kg (Davies and Morris, 1993), R B = 0.627 (Izumi et al., 1996), f up forSS and SR = 0.0031 andf up for RS and RR = 0.0035 (Izumi et al., in press).

  • 2-b Calculated using a model involving epimerization at the 5-position of thiazolidine ring from in vivo plasma profiles. Data represent the estimate value ± calculated S.D. (Izumi et al., in press).

  • 2-c Ratio of in vitro value to in vivovalue.

  • 2-d CL H based on dispersion model was calculated from equations 5 and 6 with Q H = 90 ml/min/kg (Davies and Morris, 1993), R B = 0.627 (Izumi et al., 1996) and f up = 0.00264 (Izumi et al., 1996).

  • 2-e CL H,Sulf. and CL H,Glu.were calculated from equations 7 and 8, respectively.

  • 2-f Calculated as follows: CL H,Sulf. =CL tot × (sum of fractional urinary and biliary excretion data of sulfate conjugate); CL H,Glu. =CL tot × (sum of fractional urinary and biliary excretion data of glucuronide conjugate).

  • 2-g Calculated by in vitro CL H/CL tot.

  • 2-h CL H based on dispersion model was calculated from equations 5 and 6 with Q H = 55 ml/min/kg (Davies and Morris, 1993), R B = 0.593 (Izumi et al., 1996) and f up = 0.000920 (Izumi et al., 1996).

  • 2-i Data represent mean ± S.D. of four experiments.