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Titolo:
Screening for inhibitory effects of antineoplastic agents on CYP3A4 in human liver microsomes
Autore:
Baumhakel, M; Kasel, D; Rao-Schymanski, RA; Bocker, R; Beckurts, KT; Zaigler, M; Barthold, D; Fuhr, U;
Indirizzi:
Univ Cologne, Inst Pharmakol, Klin Pharmakol, D-50931 Cologne, Germany Univ Cologne Cologne Germany D-50931 Pharmakol, D-50931 Cologne, Germany Univ Erlangen Nurnberg, Dept Expt & Clin Pharmacol & Toxicol, D-8520 Erlangen, Germany Univ Erlangen Nurnberg Erlangen Germany D-8520 D-8520 Erlangen, Germany Univ Cologne, Dept Visceral & Vasc Surg, D-50931 Cologne, Germany Univ Cologne Cologne Germany D-50931 Vasc Surg, D-50931 Cologne, Germany
Titolo Testata:
INTERNATIONAL JOURNAL OF CLINICAL PHARMACOLOGY AND THERAPEUTICS
fascicolo: 12, volume: 39, anno: 2001,
pagine: 517 - 528
SICI:
0946-1965(200112)39:12<517:SFIEOA>2.0.ZU;2-#
Fonte:
ISI
Lingua:
ENG
Soggetto:
PHARMACOKINETIC DRUG-INTERACTIONS; PHASE-I TRIAL; CLINICAL PHARMACOKINETICS; CYTOCHROME-P450 3A4; BREAST-CANCER; LIQUID-CHROMATOGRAPHY; ANTICANCER DRUGS; VINCA-ALKALOIDS; HUMAN-PLASMA; MITOMYCIN-C;
Keywords:
antineoplastic agents; CYP3A4; cytochrome P450; drug interaction; polychemotherapy regimen;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
59
Recensione:
Indirizzi per estratti:
Indirizzo: Fuhr, U Univ Cologne, Inst Pharmakol, Klin Pharmakol, Gleueler Str 24, D-50931 Cologne, Germany Univ Cologne Gleueler Str 24 Cologne Germany D-50931gne, Germany
Citazione:
M. Baumhakel et al., "Screening for inhibitory effects of antineoplastic agents on CYP3A4 in human liver microsomes", INT J CL PH, 39(12), 2001, pp. 517-528

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 examinetheir inhibitory potency on CYP3A4 with regard to possible mutual drug interactions. Method: 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 muM (= K-M). Formation of the pyridine metabolite was measured using HPLC. Inhibitor concentrations used were 0.5, 5 and 50 mug/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 mug/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 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 hydrochloride (206/200 mu mol/l), doxorubicin hydrochloride (160/215 mu mol/l), teniposide (64/84 mu mol/l) and docetaxel (6.4/12.7 mu mol/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. Conclusion: Comparing IC50 values with plasma concentrations present during antineoplastic therapy, the agentscyclophosphamide, 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.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 19/01/20 alle ore 11:44:31