IC50 values of ticlopidine towards bupropion metabolite formation in the presence and absence of a 30-minute preincubation with NADPH in HLM

IC50-values are shown with the 95% confidence intervals. OH-bupropion and 4′-OH-bupropion formation was used as a measure of CYP2B6 and CYP2C19 activity, respectively. Based on previous reports, the formation of threohydrobupropion and erythrohydrobupropion in HLM was attributed to 11β-HSD-1 (Meyer et al., 2013; Skarydova et al., 2014). Ticlopidine IC50 values were based on measured ticlopidine concentrations prior to the 7-minute bupropion incubation. Ticlopidine fu in 0.5 mg/ml HLM was 0.13, so the unbound IC50 values were 0.07 (OH-bupropion), 0.12 (4′-OH-bupropion), 1.3 (threohydrobupropion), and 1.5 µM (erythrohydrobupropion).

MetabolitePrimary EnzymeIC50 −NADPHIC50 +NADPHFold Shift
OH-bupropionCYP2B60.53 (0.40––0.70)0.07 (0.06–0.08)7.6
4′-OH-bupropionCYP2C190.87 (0.25–3.04)0.14 (0.06–0.35)6.2
Threohydrobupropion11β-HSD-111.82 (4.04–24.57)4.91 (2.41–10.02)2.4
Erythrohydrobupropion11β-HSD-110.20 (4.41–23.59)4.39 (2.10–9.29)2.3