TABLE 3

Parameters of elementary process in absorption determined by transcellular permeation and preload efflux experiments using CYP3A4-CPR-HAC/Caco-2 cells The values in parentheses represent the estimated standard deviation obtained by the fitting analysis.

ClassDrugPSPgpa,bCLMa,cPSAa,dPSBa,eRBAffentgfuhPappi
P-gpFexofenadine0.020
(0.0052)
NAj0.0019
(0.00020)
0.0043
(0.00063)
2.270.40
(0.027)
0.49
(0.30)
0.26
Digoxin0.15
(0.032)
NA0.011
(0.0010)
0.038
(0.016)
3.440.98
(0.12)
0.88
(0.15)
1.8
P-gp + CYP3AAtorvastatin0.53
(0.11)
0.00410.030
(0.0026)
0.057
(0.0082)
1.900.017
(0.00074)
0.16
(0.072)
2.3
QuinidineKm: 0.077k
(0.034)
Vmax: 0.17l
(0.40)
0.0000760.11
(0.0099)
0.12
(0.010)
1.060.0046
(0.00032)
0.59
(0.37)
4.6
CYP3ANisoldipineNA1.16
(0.21)
0.37
(0.032)
0.22
(0.056)
0.600.0035
(0.00040)
0.15
(0.088)
39
BuspironeNA0.0330.21
(0.018)
0.21
(0.027)
0.960.10
(0.0025)
0.78
(0.20)
82
FelodipineNA0.351.42
(0.058)
0.56
(0.14)
0.390.0003
(0.000035)
0.032
(0.016)
287
MidazolamNA0.100.16
(0.016)
0.19m
(0.024)
0.21
(0.021)
0.26m
(0.031)
1.38
1.37m
0.015
(0.00084)
0.024m
(0.00084)
0.10
(0.080)
60
76m
TerfenadineNA0.500.039
(0.0015)
0.042
(0.005)
1.060.0036
(0.00011)
0.42
(0.22)
2.4
NifedipineNA0.0330.19
(0.0077)
0.17
(0.020)
0.910.017
(0.00046)
0.31
(0.081)
69
SildenafilNA0.0170.079
(0.0030)
0.091
(0.014)
1.150.053
(0.0019)
0.94
(0.073)
32
RepaglinideNA0.00710.21
(0.0088)
0.51
(0.060)
2.390.021
(0.00042)
0.071
(0.032)
124
  • aUnit is mL/h/2.5 × 105 cells.

  • bPermeability surface area product (PS) for efflux by P-gp.

  • cIntrinsic metabolic clearance. The value for nisoldipine was obtained from the fitting analysis. Other values were calculated from microsomal incubations (Gertz et al., 2010) using nisoldipine as a standard.

  • dPS of A membrane for both-direction permeation.

  • ePS of B membrane for both-direction permeation.

  • fThe membrane permeability ratio of B membrane to A membrane (RBA).

  • gUnbound fraction in the enterocytes obtained from the fitting analysis.

  • hUnbound fraction in the incubation buffer containing 0.5% bovine serum albumin obtained experimentally.

  • iApparent permeability estimated from PSPgp, CLM, PSA, and PSB with eq. 5. Unit is cm/sec × 10−6.

  • jNot applicable.

  • kUnit is µM.

  • lUnit is nmol/h per 2.5 × 105 cells.

  • mEvaluated in the alternative experiment (Supplemental Methods, 1.3).