title: Screening for inhibitory effects of antineoplastic agents on CYP3A4 in human liver microsomes.
abstract: BACKGROUND
  The human cytochrome P450 enzyme CYP3A4 is involved in the metabolism 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 interactions.
  
  
  METHODS
  CYP3A4 activities in human liver microsomes from 2 donors were determined using the oxidation of the dihydropyridine denitronifedipine, a specific CYP3A4 substrate, at a concentration of 50 microM (= KM). Formation of the pyridine metabolite was measured using HPLC. Inhibitor concentrations used were 0.5, 5 and 50 microg/ml, except for cyclophosphamide and ifosfamide (0.5, 2.5 and 5 mg/ml) and for paclitaxel (0.05, 0.15, 0.5, 1.5 and 5 microg/ml).
  
  
  RESULTS
  The following substances showed an inhibitory effect on CYP3A4 (IC50 values for the 2 microsome samples are parenthesized): cyclophosphamide (12.3/9.2 mmol/l), mafosfamide generated 4-OH-cyclophosphamide (152/163 [micromol/l), ifosfamide (3.6/2.5 mmol/l), vinblastine sulfate (20/44 micromol/l), vincristine sulfate (67/176 micromol/l), daunorubicin hydrochloride (206/200 micromol/l), doxorubicin hydrochloride (160/215 micromol/l), teniposide (64/84 micromol/l) and docetaxel (6.4/12.7 micromol/l). No inhibitory effect on CYP3A4 was observed with epirubicin, etoposide, paclitaxel, cytarabine, 5-FU, 6-mercaptopurine, methotrexate, cisplatin, carboplatin, bleomycin, busulfan, chlorambucil and mitomycin.
  
  
  CONCLUSIONS
  Comparing IC50 values with plasma concentrations present during antineoplastic therapy, the agents cyclophosphamide, ifosfamide, vinblastine, teniposide and docetaxel could possibly cause clinical drug interactions by inhibition of CYP3A4. Some recently described clinical interactions with antineoplastic agents may be explained by these results.
authors.affiliation: Clinical Pharmacology, Institute for Pharmacology, University of Köln, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Baumhäkel
authors.forename: D
authors.initials: D
authors.lastname: Kasel
authors.forename: R A
authors.initials: RA
authors.lastname: Rao-Schymanski
authors.forename: R
authors.initials: R
authors.lastname: Böcker
authors.forename: K T
authors.initials: KT
authors.lastname: Beckurts
authors.forename: M
authors.initials: M
authors.lastname: Zaigler
authors.forename: D
authors.initials: D
authors.lastname: Barthold
authors.forename: U
authors.initials: U
authors.lastname: Fuhr
mesh_terms: D000465:Algorithms; D000970:Antineoplastic Agents / Q000097:blood / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D006801:Humans; D020128:Inhibitory Concentration 50; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008970:Molecular Weight; D009543:Nifedipine / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D009543:Nifedipine