Results of chemical inhibition studies of amitriptyline biotransformation by human liver microsomes and SUPERMIX at substrate concentrations of 1.5 and 15 μM
| Pathway | Inhibitor (Concentration) | Target CYP | Human Livers | SUPERMIX | ||
|---|---|---|---|---|---|---|
| FDV at 1.5 μM | FDV at 15 μM | FDV at 1.5 μM | FDV at 15 μM | |||
| N-Demethylation | α-Naphthoflavone (1 μM) | 1A2 | 0.189 ± 0.09 | 0.23 ± 0.14 | 0.379 | 0.277 |
| (0.042–0.377) | (0.058–0.503) | |||||
| Sulfaphenazole (10 μM) | 2C9 | 0.112 ± 0.05 | 0.11 ± 0.07 | 0.151 | 0.256 | |
| (0.024–0.192) | (0.016–0.192) | |||||
| Omeprazole (10 μM) | 2C19 | 0.453 ± 0.11 | 0.288 ± 0.08 | 0.682 | 0.654 | |
| (0.294–0.614) | (0.148–0.373) | |||||
| S-Mephenytoin (500 μM) | 2C19 | 0.37 ± 0.16 | 0.292 ± 0.09 | 0.425 | 0.296 | |
| (0.064–0.587) | (0.115–0.377) | |||||
| Quinidine (5 μM) | 2D6 | 0.056 ± 0.04 | 0.099 ± 0.03 | 0.336 | 0.182 | |
| (0.005–0.156) | (0.03–0.131) | |||||
| TAO (100 μM) | 3A4 | 0.129 ± 0.12 | 0.307 ± 0.16 | 0.178 | 0.268 | |
| (0–0.336) | (0.091–0.529) | |||||
| Ketoconazole (2.5 μM) | 3A4 | 0.405 ± 0.07 | 0.432 ± 0.11 | 0.448 | 0.497 | |
| (0.316–0.531) | (0.303–0.617) | |||||
| E-10 hydroxylation | Quinidine (5 μM) | 2D6 | 0.832 ± 0.06 | 0.624 ± 0.1 | 1.0 | 0.714 |
| (0.723–0.939) | (0.454–0.838) | |||||
| TAO (100 μM) | 3A4 | N.D. | 0.271 ± 0.16 | N.D. | 0.372 | |
| (0.041–0.492) | ||||||
| Ketoconazole (2.5 μM) | 3A4 | 0.14 ± 0.08 | 0.227 ± 0.16 | 0.372 | 0.501 | |
| (0.04–0.273) | (0.056–0.432) | |||||
FDV is presented. Table entries are means ± S.D., with the range of values in parentheses. Data from CYP2C19 and 2D6 poor metabolizer livers were excluded in calculating means and range of values forN-demethylation; data from the CYP2D6 deficient liver was excluded for E-10 hydroxylation (n = 9 human livers forN-demethylation, n = 11 human livers for E-10 hydroxylation).
N.D., not determined.