Inhibition of efavirenz metabolism by P450 isoform-specific inhibitors in HLMs and recombinant human CYP2B6
Efavirenz (10 μM) was reconstituted in phosphate buffer (pH 7.4) and incubated at 37°C for 30 min with microsomes from human liver or recombinant CYP2B6 and NADPH-generating system in the presence or absence of specific inhibitors.
MI | MIIa (HLMs) | MIII | |||||
|---|---|---|---|---|---|---|---|
| HLMs | CYP2B6 | HLMs | CYP2B6 | ||||
| Control (no inhibitor) | 100 | 100 | 100 | 100 | 100 | ||
| Furafylline (20 μM) | 97 ± 9.8 | 108.5 | 103.8 ± 3.7 | 92.0 ± 7.9 | 88.4 | ||
| thioTEPA (50 μM) | 35 ± 1.3 | 40 ± 3.5 | 143.3 ± 5 | 25 ± 1.6 | 22 | ||
| Sulfaphenazole (20 μM) | 80.6 ± 3.6 | 107.7 | 56 ± 5.1 | 92.2 ± 4.8 | 89.3 | ||
| Omeprazole (10 μM) | 80.6 ± 5.7 | 107.1 | 58.7 ± 1.4 | 83.5 ± 1.6 | 100.3 | ||
| Quinidine (1 μM) | 83.9 ± 1.9 | 97.5 | 79.2 ± 18.6 | 95.8 ± 0.5 | 95.3 | ||
| Diethyldithiocarbamate (50 μM) | 94.4 ± 13.9 | 115.3 | 64.9 ± 16 | 89.4 ± 11.9 | 72.4 | ||
| Ketoconazole (1 μM) | 82.8 ± 4.2 | 104.7 | 100.5 ± 16.4 | 86.3 ± 4.4 | 80.2 | ||
| Troleandomycin (50 μM) | 101.8 ± 10.9 | 101.0 | 48.6 ± 6.9 | 80.7 ± 6.2 | 109.9 | ||
↵ a MII was formed in HLMs, but not by CYP2B6. Inhibition data in HLMs are presented as mean ± S.D. (n = at least 3 independent experiments in duplicate), whereas the data from CYP2B6 are given as average of duplicate measurements.