Correlation of various CYP-selective monooxygenase activities with the hydroxylation of ABT-761 and ABT-438 in a panel of human liver microsomes
| Reaction1-a | CYP Form(s) | Correlation Coefficient | |
|---|---|---|---|
| ABT-761 | ABT-438 | ||
| TOLase | CYP2C9 | 0.631-b | 0.61 |
| COHase | CYP2A6 | 0.741-c | 0.731-c |
| ERODase | CYP1A2 | 0.31 | 0.32 |
| DMNase | CYP2E1 | 0.14 | 0.13 |
| DEXase | CYP2D6 | 0.601-b | 0.59 |
| ERNDase | CYP3A | 0.831-c | 0.831-c |
| CYP2D61-d | CYP2D6 | 0.50 | 0.49 |
| MEPHase | CYP2C19 | 0.861-e | 0.871-e |
| Total CYP1-f | 0.921-e | 0.921-e | |
| ABT-438 hydroxylation | 0.991-e | ||
| Zileuton sulfoxidation (S1) | CYP3A/CYP2C9 | 0.971-e | 0.981-e |
| Zileuton sulfoxidation (S2) | CYP3A/CYP2C9 | 0.971-e | 0.981-e |
| Zileuton hydroxylation | CYP1A2/CYP2C9 | 0.47 | 0.46 |
| ABT-193 sulfoxidation | CYP3A/CYP2C9 | 0.971-e | 0.981-e |
| ABT-193 hydroxylation | CYP1A2/CYP2C9 | 0.56 | 0.53 |
The correlation coefficients were determined with liver tissue from 11 different organ donor subjects, except for correlations involving tolbutamide hydroxylase (N = 10). The final concentration of ABT-761 and ABT-438 used in the analysis was 10 μM.
↵1-a TOLase, tolbutamide hydroxylase; COHase, COU hydroxylase; ERODase, 7-ethoxyresorufin O-deethylase; DMNase,N,N-dimethylnitrosamine N-demethylase; DEXase, dextromethorphan O-demethylase; ERNDase, erythromycinN-demethylase; MEPHase, (S)-(+)-mephenytoin 4′-hydroxylase.
↵1-b p < 0.05.
↵1-c p < 0.01.
↵1-d The levels of CYP2D6 apoprotein were measured using an enzyme-linked immunosorbent assay procedure.
↵1-e p < 0.001.
↵1-f Total (spectrally detectable) CYP.