Screening for inhibitory effects of antineoplastic agents on CYP3A4 in human liver microsomes

Background: The human cytochrome P450 enzyme CYP3A4 is involved in the meta bolism of many anticancer drugs. Since these drugs are usually administered in a polychemotherapy regimen, the objective of this study was to examine their inhibitory potency on CYP3A4 with regard to possible mutual drug inte ractions. Method: CYP3A4 activities in human liver microsomes from 2 donors were determined using the oxidation of the dihydropyridine denitronifedipi ne, a specific CYP3A4 substrate, at a concentration of 50 muM (= K-M). Form ation of the pyridine metabolite was measured using HPLC. Inhibitor concent rations used were 0.5, 5 and 50 mug/ml, except for cyclophosphamide and ifo sfamide (0.5, 2.5 and 5 mg/ml) and for paclitaxel (0.05, 0.15, 0.5, 1.5 and 5 mug/ml). Results: The following substances showed an inhibitory effect o n CYP3A4 (IC50 values for the 2 microsome samples are parenthesized): cyclo phosphamide (12.3/9.2 mmol/l), mafosfamide generated 4-OH-cyclophosphamide (152/163 mu mol/l), ifosfamide (3.6/2.5 mmol/l), vinblastine sulfate (20/44 mu mol/l), vincristine sulfate (67/176 mu mol/l), daunorubicin hydrochlori de (206/200 mu mol/l), doxorubicin hydrochloride (160/215 mu mol/l), tenipo side (64/84 mu mol/l) and docetaxel (6.4/12.7 mu mol/l). No inhibitory effe ct on CYP3A4 was observed with epirubicin, etoposide, paclitaxel, cytarabin e, 5-FU, 6-mercaptopurine, methotrexate, cisplatin, carboplatin, bleomycin, busulfan, chlorambucil and mitomycin. Conclusion: Comparing IC50 values wi th plasma concentrations present during antineoplastic therapy, the agents cyclophosphamide, ifosfamide, vinblastine, teniposide and docetaxel could p ossibly cause clinical drug interactions by inhibition of CYP3A4. Some rece ntly described clinical interactions with antineoplastic agents may be expl ained by these results.