Table 2.
Metoprolol metabolism by human liver microsomes in the absence (w/o) and presence of inhibitors.
| Metabolite formed | w/o inhibitor fmol/min/pmol CYP | with inhibitor fmol/min/pmol CYP | % residual activity (quinidine) or % inhibition (ketoconazole, ticlopidine, sulfaphenazole, (+)-N-3-benzylnirvanol) |
|---|---|---|---|
| Quinidine 1 μM (CYP2D6) | |||
| O-demethyl-MTP | 17.5 ± 0.3 | 3.32 ± 0.40 | 19.0 ± 2.1 (2.6) |
| α-OH-MTP | 4.11 ± 0.06 | 0.16 ± 0.06 | 4.0 ± 0.6 (0.70) |
| MTP-phenylacetate | 0.91 ± 0.0.05 | 0 | 0 |
| N-dealkyl-MTP | 2.91 ± 0.06 | 0.22 ± 0.05 | 7.6 ± 1.7 (2.1) |
| Ketoconazole 1 μM (CYP3A4) | |||
| O-demethyl-MTP | 26.6 ± 0.0.6 | 22.0 ± 0.0.8 | 17.5 ± 3.4 (4.3) |
| α-OH-MTP | 6.86 ± 0.0.23 | 5.71 ± 0.29 | 16.8 ± 2.4 (3.0) |
| N-dealkyl-MTP | 4.86 ± 0.29 | 4.38 ± 0.23 | 9.9 ± 1.7 (2.1) |
| Ticlopidine 1 μM (CYP2B6) | |||
| O-demethyl-MTP | 30.3 ± 3.3 | 24.2 ± 0.34 | 20.2 ± 8.0 (9.9) |
| α-OH-MTP | 7.43 ± 1.14 | 5.71 ± 0.0.29 | 23.2 ± 11.1 (13.7) |
| N-dealkyl-MTP | 4.97 ± 1.03 | 3.74 ± 0.23 | 24.8 ± 12.7 (15.8) |
| Sulfaphenazole 10 μM (CYP2C9) | |||
| O-demethyl-MTP | 27.7 ± 0.40 | 20.3 ± 2.4 | 26.5 ± 10.4 (13.2) |
| α-OH-MTP | 6.40 ± 0.23 | 4.67 ± 0.57 | 27.0 ± 9.8 (12.2) |
| N-dealkyl-MTP | 4.51 ± 0.0.46 | 3.83 ± 0.74 | 15.2 ± 14.5 (18.0) |
| (+)-N-3-benzylnirvanol 10 μM (CYP2C19) | |||
| O-demethyl-MTP | 25.8 ± 0.6 | 25.0 ± 1.43 | 3.1 ± 8.4 (10.4) |
| α-OH-MTP | 6.23 ± 0.23 | 6.23 ± 0.0.34 | 0 |
| N-dealkyl-MTP | 4.29 ± 0.17 | 4.29 ± 0.23 | 0 |
Metoprolol metabolites were determined by LC/MS as described in the Section “Materials and Methods.” Activity is given as pmol/min/pmol CYP. Data are given as mean ± SD and 95%CI in parentheses for residual activity. CYP: cytochrome P450 enzyme, MTP: metoprolol.