TABLE 5
Fitted estimates obtained with fitting the final model (Model H) to liver perfusion data (Table 4), with incorporation of nonlinear protein binding and nonlinear metabolism and biliary secretion of verapamil and norverapamil (see Appendix C for the mass balance equations)
| Assigned Parameter, Mean ± S.D. (CV%) | ||||
|---|---|---|---|---|
| Verapamil (VER, racemic) (μM) (n = 4) | 1 μM | 50 μM | 100 μM | |
| Volume of sinusoid, V LB (ml) a | 2.79 ± 0.23 | 2.70 ± 0.16 | 2.26 ± 0.12 | |
| Volume of liver tissue, V L (ml) a | 8.16 ± 0.68 | 10.6 ± 0.6 | 7.56 ± 0.41 | |
| Norverapamil (NOR, racemic) (μM) | 1.5 μM | 5 μM | ||
| Volume of sinusoid, V LB (ml) a | 2.93 ± 0.08 (2.73) | 2.35 ± 0.15 (6.38) | ||
| Volume of liver tissue, V L (ml) a | 8.57 ± 0.22 (2.57) | 9.23 ± 0.59 (6.39) | ||
| Fitted Parameter | ||||
: unbound fraction of VER in liver tissue | 0.0878 ± 0.0050 (5.69) | |||
: unbound fraction of NOR in liver blood perfusate | 0.44 ± 0.05 (11.3) | |||
: unbound fraction of NOR in liver tissue | 0.00874 ± 0.00046 (5.26) | |||
: influx and efflux clearances of VER (ml/min) | 526 ± 96 (18.3) | |||
and
: influx and efflux clearances for NOR (ml/min) | 482 ± 181 (37.6) | |||
: intrinsic formation clearance of NOR from VER under linear conditions (ml/min) |
(34.6) nmol/min | |||
(38.9) μM | ||||
: metabolic intrinsic clearance of VER to form other metabolites under linear conditions (ml/min) |
(17.7) nmol/min | |||
(34.7) μM | ||||
: metabolic intrinsic clearance of NOR under linear conditions (ml/min) | 36.5 ± 18.4 (50.4) | |||
: biliary intrinsic clearance of VER under linear conditions (ml/min) |
(55.4) nmol/min | |||
(48.2) μM | ||||
: biliary intrinsic clearance of NOR under inear conditions (ml/min) |
(28.4) nmol/min | |||
(31.0) μM | ||||
| τ: time delay for biliary secretion (minute) | 4.49 ± 1.41 (31.4) | |||
b
| 0.311 ± 0.189 | |||
| 0.683 ± 0.341 | |||
| 0.0064 ± 0.0051 | |||