Effects of selected solvents on the kinetic parameters of (S)-warfarin and midazolam hydroxylation in HLMs
| (S)-Warfarin 7-Hydroxylation | Midazolam 1′-Hydroxylation | |||||||
|---|---|---|---|---|---|---|---|---|
| Km | Vmax | Clint,liver | ClH | S50 | Vmax | Clmax,liver | ClH | |
| μM | pmol · min−1 · mg−1 | ml · min−1 · kg−1 | μM | nmol · min−1 · mg−1 | ml · min−1 · kg−1 | |||
| Water | 6.8 ± 0.7 | 10.7 ± 0.7 | 3.1 | 0.031 | 3.7 ± 0.6 | 2.8 ± 0.3 | 550 | 5.5 |
| Acetonitrile | ||||||||
| 0.1% | 5.8 ± 0.6 | 7.3 ± 0.4* | 2.5 | 0.025 | 2.3 ± 0.2 | 2.5 ± 0.1 | 720 | 6.2 |
| 1% | 7.7 ± 0.9 | 5.9 ± 0.5† | 1.5 | 0.015 | 4.7 ± 0.7‡ | 2.9 ± 0.3 | 440 | 4.9 |
| 2% | 7.8 ± 0.9 | 4.3 ± 0.4†,‡ | 1.1 | 0.011 | 4.3 ± 0.4 | 2.2 ± 0.1 | 360 | 4.4 |
| Methanol | ||||||||
| 0.1% | 5.9 ± 0.6 | 8.1 ± 0.5* | 2.7 | 0.027 | 3.1 ± 0.3 | 2.4 ± 0.1 | 520 | 5.4 |
| 1% | 7.9 ± 0.9 | 4.9 ± 0.4†,‡ | 1.3 | 0.013 | 3.3 ± 0.4 | 2.3 ± 0.2 | 480 | 5.1 |
| 2% | 13.8 ± 1.6*,‡,§ | 3.7 ± 0.3†,‡ | 0.54 | 0.005 | 4.3 ± 0.7 | 2.5 ± 0.3 | 400 | 4.6 |
| Ethanol | ||||||||
| 0.1% | 3.8 ± 0.4 | 3.2 ± 0.2 | 600 | 5.8 | ||||
| 1% | 4.9 ± 0.6 | 3.7 ± 0.3 | 550 | 5.5 | ||||
| 2% | 5.5 ± 0.6 | 3.5 ± 0.3 | 460 | 5.0 | ||||
Clint,liver, whole-liver intrinsic clearance; Clmax,liver, whole-liver maximum intrinsic clearance; ClH, predicted in vivo hepatic plasma clearance.
↵* P < 0.050 versus water (one-way ANOVA, followed by Tukey's test).
↵† P < 0.001 versus water (one-way ANOVA, followed by Tukey's test).
↵‡ P < 0.050 versus 0.1% (one-way ANOVA, followed by Tukey's test).
↵§ P < 0.050 versus 1% (one-way ANOVA, followed by Tukey's test).