TABLE 3

Inhibition of efavirenz 7- and 8-hydroxylation by thioTEPA, pilocarpine, and ticlopidine in HLM samples and expressed CYP2A6 and CYP2B6

Efavirenz (10 μM) was incubated for 10 min at 37°C in duplicate with HLM samples (0.25 mg/ml) (or 26 pmol of CYP2A6 or 13 pmol of CYP2B6) and cofactors in the absence (control) and presence of an inhibitor. For determination of percentage activity remaining, a single concentration of thioTEPA (50 μM), pilocarpine (50 μM), or ticlopidine (5 μM) was used. To determine the IC50 values, multiple concentrations of thioTEPA (0–100 μM) or pilocarpine (0–100 μM) were used.

InhibitorMicrosomes7-Hydroxylation8-Hydroxylation
%Activity RemainingIC50%Activity RemainingIC50
μMμM
ThioTEPA
HLMs55.0 ± 1.431.732.3 ± 4.39.8
CYP2A617.4 ± 0.66.617.5 ± 1.46.9
CYP2B644.9 ± 0.2
Pilocarpine
HLMs4.3 ± 1.92.332.7 ± 0.829.5
CYP2A65.8 ± 0.56.2 ± 0.4
CYP2B675.6 ± 4.2135.6
Ticlopidine
HLMs150.8 ± 11.118.1 ± 0.6
CYP2A677.5 ± 6.477.8 ± 6.2
CYP2B627.0 ± 0.5