Effects of chemical modulators on the 4′- and 10-hydroxylation of warfarin3-a
| Modulator | Concentration | Enzyme Sources | 4′-HydroxylationS-Warfarin3-b | 10-HydroxylationR-Warfarin3-b |
|---|---|---|---|---|
| μM | % Control | % Control | ||
| Quinidine | 50 | HLM | 380 | 500 |
| Quinidine | 10–50 | 3A4 | 150–200 | 200–350 |
| Quinine | 50 | HLM | 230 | 300 |
| Epiquinidine | 50 | HLM | 310 | 300 |
| Epiquinine | 50 | HLM | 230 | 260 |
| 3-Hydroxyquinidine | 50 | HLM | 110 | 280 |
| QuinidineN-oxide | 50 | HLM | 60 | 80 |
| 7,8-Benzoflavone | 20–100 | HLM | 25–10 | 25–5 |
| S-Warfarin | 10–300 | HLM | 90–60 | |
| R-Warfarin | 5–250 | HLM | 90–70 |
HLM, pooled human liver microsomes; 3A4, recombinant CYP3A4.
↵3-a Warfarin and chemical modulators in methanol were added to human liver microsomes or recombinant CYP3A4 suspended in phosphate buffer (0.1 M, pH 7.4) containing EDTA. The concentration of warfarin was 50 μM. Controls contained no modulator but the same amount of methanol. Incubations were performed in duplicates.
↵3-b % Control was based on the formation of hydroxylated warfarin derivatives in test incubations relative to the values in control experiments that lacked modulator.