TABLE 3.
Correlation analysis (r) of the relationship between the rates of metronidazole conversion to 2-hydroxymetronidazole with the sample-to-sample variation in cytochrome P450 activity in human liver microsomes
Values in bold indicate significant correlations between P450 activity and 2-hydroxymetronidazole formation at P < 0.05. Coumarin 7-hydroxlation was significantly correlated (r, P value) with S-mephenytoin N-hydroxylation (0.703, 0.001) and bupropion hydroxylation (0.576, 0.018).
| 2-Hydroxymetronidazole Formation |
||||
|---|---|---|---|---|
| Enzymatic Reaction (Enzyme) | 100-μM Metronidazole a |
300-μM Metronidazole a |
||
| r | P | r | P | |
| 7-Ethoxyresorufin O-deethylation (CYP1A2) | 0.032 | 0.906 | 0.068 | 0.801 |
| Phenacetin O-deethylation (CYP1A2) | 0.107 | 0.692 | 0.128 | 0.635 |
| Coumarin 7-hydroxylation (CYP2A6) | 0.970 | 9.19 × 10−11 | 0.972 | 5.17 × 10−11 |
| S-Mephenytoin N-hydroxylation (CYP2B6) | 0.742 | 0.001 | 0.703 | 0.002 |
| Bupropion hydroxylation (CYP2B6) | 0.648 | 0.006 | 0.618 | 0.010 |
| Paclitaxel 6α-hydroxylation (CYP2C8) | 0.421 | 0.102 | 0.395 | 0.127 |
| Diclofenac 4′-hydroxylation (CYP2C9) | 0.181 | 0.502 | 0.165 | 0.540 |
| S-Mephenytoin 4′-hydroxylation (CYP2C19) | 0.419 | 0.010 | 0.375 | 0.149 |
| Dextromethorphan O-demethylation (CYP2D6) | −0.072 | 0.791 | −0.112 | 0.679 |
| Chlorzoxazone 6-hydroxylation (CYP2E1) | −0.106 | 0.695 | −0.102 | 0.706 |
| Testosterone 6β-hydroxylation (CYP3A4/5) | 0.282 | 0.288 | 0.221 | 0.410 |
| Midazolam 1′-hydroxylation (CYP3A4/5) | 0.298 | 0.260 | 0.245 | 0.359 |
| Lauric acid 12-hydroxylation (CYP4A9/11) | −0.218 | 0.415 | −0.214 | 0.424 |
r, Correlation coefficient.
a
Concentration of metronidazole present in microsomal incubations.