Inhibition of microsomal biotransformation of deramciclane by P450-specific inhibitors
Liver microsomes (1.5 mg/ml) were incubated with 50 μM deramciclane in the absence or presence of P450 form-specific inhibitors (αNF, α-naphthoflavone; SF, sulfaphenazole; QUIN, quinidine; DDC, diethyl-dithiocarbamate; TAO, troleandomycin). The metabolites were separated on a thin-layer plate using ethyl acetate/triethylamine (25:1, v/v). The amounts of metabolites are presented as the percentage of uninhibited activity.
Metabolite | αNF | SF | QUIN | DDC | TAO |
|---|---|---|---|---|---|
| Rat | |||||
| N-Desmethyl 9-hydroxy-deramciclane (M2) | 63.0 ± 10.6a* | 375.2 ± 108.6* | 138.4 ± 8.9* | ND** | 72.3 ± 12.2 |
| N-Desmethyl hydroxy-deramciclane II (M3) | 57.5 ± 16.3 | 64.0 ± 14.9 | 85.4 ± 20.7 | ND** | 61.6 ± 17.5 |
| N-Desmethyl deramciclane (M4) | 83.2 ± 22.7 | 120.4 ± 17.4 | 136.0 ± 18.3 | 48.7 ± 18.8* | 125.3 ± 34.0 |
| 9-Hydroxy-deramciclane (M5) | 72.1 ± 6.7 | 85.3 ± 12.3 | 106.9 ± 25.3 | 60.9 ± 7.6** | 85.2 ± 16.8 |
| Hydroxy-deramciclane II (M6) | 78.5 ± 22.6 | 88.8 ± 45.3 | 130.3 ± 12.5 | ND** | 76.7 ± 17.7 |
| Phenylborneol (M8) | 62.3 ± 3.3* | 31.4 ± 14.3** | 62.33 ± 21.65 | ND** | 52.4 ± 6.3* |
| Human | |||||
| N-Desmethyl deramciclane (M4) | 94.6 ± 2.9 | 84.4 ± 10.5 | 116.6 ± 15.8 | 66.8 ± 5.3** | 88.8 ± 5.2 |
| Phenylborneol (M8) | 38.0 ± 4.9** | 29.1 ± 3.2** | 75.1 ± 15.6 | ND** | 38.5 ± 11.5* |
ND, not detectable.
↵ a Significant changes (n = 3): *P < 0.05, **P < 0.01.