Microsomal CLin determined at different HLM concentrations and extrapolation of CLin,u
Compounds (1 μM) were incubated in the presence of NADPH with five different concentrations of pooled HLMs (0.1, 0.2, 0.5, 1, or 2 mg/ml), and intrinsic clearance values (mean ± S.D., n = 4) were obtained as described under Materials and Methods. Data were fitted by linear regression analysis according to eq. 11, and 1/CLin,u was calculated by extrapolation to zero microsome concentration. Standard errors of 1/CLin,u were derived from those of 1/CLin,u as calculated by the curve fitting software.
Drug | CLin | Linear Regression | r2 | CLin,u | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 2 mg/ml | 1 mg/ml | 0.5 mg/ml | 0.2 mg/ml | 0.1 mg/ml | ||||||||
| μl/min/mg | μl/min/mg | |||||||||||
| Desipramine | 5 ± 1 | 10 ± 1 | 14 ± 1 | 21 ± 2 | 29 ± 1 | y = 0.0931x + 0.0244 | 0.98 | 41 ± 12 | ||||
| Amitryptiline | 17 ± 1 | 34 ± 3 | 48 ± 2 | 71 ± 5 | 76 ± 3 | y = 0.0238x + 0.0092 | 0.99 | 108 ± 16 | ||||
| Imipramine | 14 ± 2 | 25 ± 3 | 32 ± 3 | 44 ± 3 | 59 ± 2 | y = 0.0271x + 0.0167 | 0.99 | 59 ± 6 | ||||
| Verapamil | 73 ± 2 | 118 ± 9 | 153 ± 4 | 185 ± 3 | 187 ± 6 | y = 0.0045x + 0.0045 | 0.99 | 222 ± 15 | ||||
| Diltiazem | 18 ± 2 | 31 ± 2 | 28 ± 2 | 33 ± 1 | 36 ± 2 | y = 0.0133x + 0.0262 | 0.88 | 38 ± 4 | ||||
| Propafenone | 70 ± 4 | 87 ± 3 | 132 ± 4 | 168 ± 7 | 172 ± 1 | y = 0.0054x + 0.0047 | 0.96 | 185 ± 21 | ||||
| Chlorpromazine | 27 ± 1 | 52 ± 1 | 84 ± 1 | 113 ± 3 | 128 ± 3 | y = 0.0154x + 0.0052 | 0.99 | 191 ± 33 | ||||
| Midazolam | 196 ± 9 | 238 ± 6 | 287 ± 9 | 319 ± 22 | 318 ± 21 | y = 0.0011x + 0.0030 | 0.99 | 333 ± 11 | ||||
| Diclofenac | 194 ± 10 | 225 ± 7 | 294 ± 8 | 349 ± 45 | 320 ± 21 | y = 0.0012x + 0.0029 | 0.94 | 344 ± 24 | ||||
r, correlation coefficient of the linear fit.