Effects of quinidine on the 4′- and 10-hydroxylation of warfarin in incubations with human liver microsomes or hepatocytes
| Incubation System1-b | CYP3A4 Activity | 10-Hydroxylation1-a | 4′-Hydroxylation1-a | ||
|---|---|---|---|---|---|
| Control | +Quinidine | Control | +Quinidine | ||
| nmol/min/mg1-c | pmol/min/mg | % Control | pmol/min/mg | % Control | |
| HLM160 (M) | 0.5 | 1.0 | 670 | 0.5 | 100 |
| HLM162 (M) | 2.3 | 7.2 | 520 | 0.9 | 270 |
| HLM163 (M) | 0.9 | 3.0 | 500 | 0.5 | 240 |
| HLM166 (F) | 2.4 | 3.0 | 870 | 0.4 | 420 |
| HLM167 (F) | 3.2 | 16.2 | 440 | 2.2 | 220 |
| HLM mixture | 1.8 | 6.4 | 500 | 0.9 | 350 |
| HLcell-1 (F) | 225 | 210 | |||
| HLcell-2 (F) | 470 | 250 | |||
| HLcell-3 (M) | 240 | 270 | |||
↵1-a For incubations with human liver microsomes, warfarin (racemic) in methanol and quinidine in water were added to a final concentration of 100 μM. For incubations with human hepatocytes, warfarin (racemic) in dimethyl sulfoxide and quinidine in water were added to a final concentration of 50 μM. Controls contained no quinidine but the same amount of methanol or dimethyl sulfoxide. Incubations were performed in duplicates. % Control was based on the formation of 4′- and 10-hydroxywarfarin in test incubations relative to the values in control experiments that lacked quinidine.
↵1-b HLM160 to 167 represent liver microsomal preparations from three male (M) and two female (F) donors; HLM mixture represents pooled liver microsomes; HLcell represents hepatocytes from male (M) or female (F) donors.
↵1-c The activity of CYP3A4 in human liver microsomes was evaluated based on the 6β-hydroxylation of testosterone.