Microsomal and hepatocyte CLint and CLH predictions and observed values for eight benzodiazepines
Values are mean ± S.D. (n = 4-8).
Compound | Log P | Microsomesa | Hepatocytesb | In vivo | fup | Blood/Plasma Ratio | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| In Vitro CLint(u) | Microsomal fu | Predicted CLint | Predicted CLH | In Vitro CLint | Predicted CLint | Predicted CLH | Observed CLint | Observed CLHc | ||||||||||
| μl/min/mg | ml/min | μl/min/106 cells | ml/min | ml/min | ||||||||||||||
| Alprazolam | 2.48 | 42 ± 20 | 1 | 27 ± 13 | 4.8 ± 1.9 | 30 ± 17 | 36 ± 21 | 5.8 ± 2.5 | 103 | 12 | 0.35 | 1.6 | ||||||
| Chlordiazepoxide | 2.44 | 4.5 ± 1.1 | 1d | 3.0 ± 0.7 | 0.3 ± 0.07 | 9.6 ± 4.7 | 12 ± 5.6 | 1.2 ± 0.6 | 18 | 1.8 | 0.15 | 1.4 | ||||||
| Clobazam | 0.95 | 110 ± 34 | 1d | 73 ± 22 | 8.1 ± 1.6 | 27 ± 13 | 32 ± 16 | 4.3 ± 1.8 | 50 | 6.3 | 0.21 | 1.3 | ||||||
| Clonazepam | 2.40 | 97 ± 9.7 | 0.76 | 64 ± 6.4 | 6.9 ± 0.5 | 17 ± 1.9 | 20 ± 2.3 | 2.7 ± 0.3 | 27 | 3.4 | 0.21 | 1.4 | ||||||
| Diazepam | 2.99 | 250 ± 72 | 0.93 | 170 ± 48 | 11 ± 1.6 | 160 ± 14 | 191 ± 16 | 12 ± 0.5 | 250 | 14 | 0.15 | 1.2 | ||||||
| Flunitrazepam | 2.06 | 87 ± 30 | 1 | 58 ± 20 | 7.8 ± 1.7 | 48 ± 32 | 57 ± 38 | 7.4 ± 3.2 | 80 | 9.8 | 0.25 | 1.2 | ||||||
| Midazolam | 3.40 | 99 ± 21 | 0.63 | 65 ± 14 | 3.8 ± 0.7 | 74 ± 11 | 88 ± 13 | 4.9 ± 0.6 | 250 | 10 | 0.07 | 1 | ||||||
| Triazolam | 2.42 | 230 ± 29 | 0.84 | 150 ± 20 | 13 ± 0.8 | 170 ± 57 | 200 ± 68 | 15 ± 1.9 | 160 | 14 | 0.28 | 1.5 | ||||||
↵ a All microsomal incubations were performed at 1 mg of protein/ml with the exception of diazepam (0.5 mg/ml).
↵ b All hepatocyte incubations were performed at 0.5 × 106 cells/ml.
↵ c Expressed as blood clearance [blood clearance = plasma clearance/(blood/plasma ratio)]; data from Ito and Houston (2004).
↵ d Values are assumed since their log P values are less than those for alprazolam and flunitrazepam.