Drug-metabolizing activities by recombinant P450 enzymes and tissue microsomes from marmosets, cynomolgus monkeys, and humans
Units of drug oxidation rates by tissue microsomes and recombinant P450 proteins are nmol/min/mg protein and nmol/min/nmol of P450, respectively. Each activity was measured at a substrate concentration of 10 μM (midazolam), 200 μM (alprazolam), 20 μM (nifedipine), 50 μM (testosterone), and 100 μM (bufuralol). Values represent the mean ± standard deviation from triplicate measurements.
| Enzyme Source | Midazolam 1′-Hydroxylation | Midazolam 4-Hydroxylation | Alprazolam 4-Hydroxylation | Nifedipine Oxidation | Testosterone 6β-Hydroxylation | Bufuralol 1′-Hydroxylation | Bufuralol 1′-Hydroxylationa |
|---|---|---|---|---|---|---|---|
| Microsomes | |||||||
| Marmoset liver | 3.6 ± 0.2 | 0.35 ± 0.03 | 0.11 ± 0.01 | 3.3 ± 0.2 | 1.6 ± 0.1 | 0.72 ± 0.02 | — |
| Cynomolgus monkey liver | 1.9 ± 0.1 | 0.49 ± 0.01 | 0.058 ± 0.002 | 3.8 ± 0.2 | 1.8 ± 0.3 | — | 1.7 |
| Human liver | 1.5 ± 0.1 | 0.13 ± 0.01 | 0.016 ± 0.002 | 2.2 ± 0.1 | 0.99 ± 0.01 | 0.24 ± 0.01 | 0.21 |
| Marmoset small intestine | 0.95 ± 0.02 | 0.075 ± 0.004 | 0.0080 ± 0.0001 | 0.32 ± 0.03 | 0.15 ± 0.02 | — | — |
| Cynomolgus monkey small intestine | 1.2 ± 0.1 | 0.29 ± 0.01 | 0.015 ± 0.001 | 1.1 ± 0.1 | 0.47 ± 0.01 | — | — |
| Human small intestine | 0.77 ± 0.01 | 0.082 ± 0.005 | 0.0085 ± 0.0002 | 1.2 ± 0.1 | 0.58 ± 0.01 | — | — |
| Recombinant P450 | |||||||
| Marmoset 3A4 ortholog | 29 ± 1 | 9.1 ± 0.6 | 1.4 ± 0.1 | 25 ± 1 | 58 ± 2 | 1.9 ± 0.2 | — |
| Marmoset 3A5 ortholog | 1.2 ± 0.1 | 0.051 ± 0.015 | 0.022 ± 0.005 | 1.1 ± 0.2 | 5.4 ± 0.3 | 1.4 ± 0.1 | — |
| Marmoset 3A90 | 3.4 ± 0.4 | 0.11 ± 0.01 | 0.054 ± 0.006 | 2.8 ± 0.1 | 4.9 ± 0.7 | 0.81 ± 0.01 | — |
| Marmoset 2D6 | — | — | — | — | — | 8.5 ± 0.9 | — |
| Marmoset 2D8 | — | — | — | — | — | 1.9 ± 0.3 | — |
| Cynomolgus monkey 3A4 | 18 ± 1 | 15 ± 1 | 1.5 ± 0.1 | 33 ± 3 | 50 ± 2 | — | 0.99 |
| Cynomolgus monkey 3A5 | 36 ± 1 | 2.7 ± 0.3 | 0.78 ± 0.01 | 34 ± 2 | 60 ± 2 | — | 2.4 |
| Cynomolgus monkey 2D6 | — | — | — | — | — | — | 8.9 |
| Cynomolgus monkey 2D44 | — | — | — | — | — | — | 4.9 |
| Human 3A4 | 11 ± 1 | 2.3 ± 0.1 | 0.74 ± 0.02 | 22 ± 2 | 20 ± 1 | 0.13 ± 0.01 | 0.41 |
| Human 3A5 | 36 ± 2 | 1.4 ± 0.1 | 0.46 ± 0.01 | 7.8 ± 0.4 | 19 ± 1 | 0.24 ± 0.01 | 0.33 |
| Human 2D6 | — | — | — | — | — | 5.8 ± 0.7 | 6.1 |
↵a Enzymatic activities for bufuralol 1′-hydroxylation by liver microsomes and recombinant P450 2D and 3A proteins at a substrate concentration of 200 μM are taken from Emoto et al. (2011).