Table 2 Physiological, experimental, and final calculated parameters for PBPK models established in this study

 Molecular weight

MW

297

313

384

372

 Octanol–water partition coefficient

logP

4.26

1.78

2.99

3.85

 Plasma unbound fraction

f_u,p

0.114

0.324

0.125

0.0732

 Blood–plasma concentration ratio

R_b

0.843

0.921

0.852

0.805

 Liver–plasma concentration ratio

K_p,h

3.18

1.17

2.69

3.01

 Fraction absorbed × intestinal availability

F_a·F_g

1

1

1

1

 Absorption rate constant

k_a (1/h)

0.372 ± 0.007^a

2.48 ± 0.05

2.86 ± 0.05

1.12 ± 0.26

 Transfer rate constant

k₁₂ (1/h)

–

0.28 ± 0.02

–

–

 Transfer rate constant

k₂₁ (1/h)

–

0.04 ± 0.01

–

–

 Volume of systemic circulation

V₁ (L)

755 ± 1^a

80.7 ± 0.1

206 ± 1

66.2 ± 9.5

 Hepatic intrinsic clearance

CL_h,int (L/h)

385 ± 1^a

15.8 ± 0.1

954 ± 1

173 ± 16

 Hepatic clearance

CL_h (L/h)

30.2

4.84

53.4

11.2

 Renal clearance

CL_r (L/h)

3.0

0.48

5.3

1.1

 C_max in plasma

ng/mL

44.9 (0.93)^b

9.12 (1.08)

44.2 (0.98)

491 (0.72)

 AUC in plasma

ng·h/mL

1210 (1.19)

52.1 (1.02)

172 (0.95)

3610 (0.77)

 C_max in plasma

ng/mL

48.5 ± 8.3^c

8.47^d

45.0^e

681 ± 128^f

 AUC in plasma

ng·h/mL

1020 ± 220

51.2

181

4670 ± 790