Effect of CYP3A4 induction and inhibition on the formation of O-debenzylated lapatinib in HepaRG cells. HepaRG cells were incubated with 100 μM dexamethasone (A) or 4 μM rifampicin (B) for 72 hours, followed by incubation with LAP (100 μM) for 24 hours. For CYP3A4 inhibition, HepaRG cells were coincubated with ketoconazole (4 μM) + LAP (100 μM). Formation of LAP-OH was quantified by LC-MS/MS utilizing MRM. Data represent the mean ± S.D. of triplicate values. ***P < 0.001 and ****P < 0.0001 for comparison of LAP versus LAP + Dex and LAP versus LAP + Rif; ƚƚƚP < 0.001 and ƚƚƚƚP < 0.0001 for comparison of LAP + Dex versus LAP + Dex + Keto and LAP + Rif versus LAP + Rif + Keto (unpaired t test, two-tailed P values). Dex, dexamethasone; Keto, ketoconazole; Rif, rifampicin.