Effect of various CYP isoform inhibitors/substrates onN-desethyl-Zaleplon formation in rat and monkey liver microsomes
| Inhibitor | Inhibitor Concentration [I] | N-Desethyl-Zaleplon Formed (% of control)2-a | |||
|---|---|---|---|---|---|
| Rat | Monkey | ||||
| Low [I] | High [I] | Low [I] | High [I] | ||
| μM | |||||
| CO | 80% (v/v) CO/O2 | 8.8 ± 2.0 | 19.8 ± 6.8 | ||
| Furafylline | 2, 20 | 91.1 ± 11.4 | 92.5 ± 6.2 | 83.0 ± 1.7 | 91.7 ± 3.9 |
| α-Naphthoflavone | 0.1 | 98.5 ± 2.7 | 94.4 ± 5.6 | ||
| Sulfaphenazole | 10, 100 | 66.7 ± 1.2 | 24.4 ± 1.1 | 69.9 ± 2.8 | 30.6 ± 0.9 |
| Tolubutamide | 10, 100 | 83.8 ± 0.9 | 92.6 ± 2.7 | 79.6 ± 1.6 | 94.3 ± 1.7 |
| (S)-(+)-Mephenytoin | 10, 100 | 83.1 ± 1.2 | 78.9 ± 2.7 | 81.0 ± 1.7 | 72.6 ± 0.9 |
| Quinidine | 10, 100 | 74.3 ± 1.1 | 29.0 ± 0.2 | 59.2 ± 1.1 | 26.1 ± 2.1 |
| Quinine | 10, 100 | 55.8 ± 0.9 | 13.7 ± 0.6 | 81.3 ± 2.8 | 44.2 ± 2.3 |
| Chlorozoxazone | 10, 100 | 90.8 ± 0.5 | 56.1 ± 2.5 | 92.1 ± 0.7 | 66.2 ± 0.4 |
| Troleandomycin | 10, 100 | 35.5 ± 0.8 | 34.2 ± 0.7 | 13.6 ± 0.6 | 14.7 ± 0.3 |
↵2-a Data are expressed as mean ± S.D. of triplicate determination and as percentage of remaining activity. Zaleplon (50 μM) was incubated at 37°C for 10 min (20 min for CO as the inhibitors) with rat and monkey liver microsomes (50 mg liver/ml) and EDTA (0.1 mM) in 0.1 M phosphate buffer (pH7.4) in the presence of NADPH (5 mM), as described in Materials and Methods. The control formed N-desethyl-Zaleplon at a rate of 6.22 ± 0.25 and 6.13 ± 0.08 nmol/g liver/ml, respectively.