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Titolo:
Effects of anticancer drugs on the metabolism of the anticancer drug 5,6-dimethylxanthenone-4-acetic (DMXAA) by human liver microsomes
Autore:
Zhou, SF; Chin, R; Kestell, P; Tingle, MD; Paxton, JW;
Indirizzi:
Univ Auckland, Sch Med, Dept Pharmacol & Clin Pharmacol, Auckland, New Zealand Univ Auckland Auckland New Zealand lin Pharmacol, Auckland, New Zealand Univ Auckland, Auckland Canc Soc Res Ctr, Auckland, New Zealand Univ Auckland Auckland New Zealand c Soc Res Ctr, Auckland, New Zealand
Titolo Testata:
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
fascicolo: 2, volume: 52, anno: 2001,
pagine: 129 - 136
SICI:
0306-5251(200108)52:2<129:EOADOT>2.0.ZU;2-S
Fonte:
ISI
Lingua:
ENG
Soggetto:
NECROSIS-FACTOR-ALPHA; FLAVONE-8-ACETIC ACID; NONSPECIFIC-BINDING; ANTITUMOR-ACTIVITY; PHARMACOKINETICS; PLASMA; ENHANCEMENT; PREDICTION; LEUKEMIA; ANALOGS;
Keywords:
anti-cancer; DMXAA; drug interaction; human liver microsomes;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
34
Recensione:
Indirizzi per estratti:
Indirizzo: Paxton, JW Univ Auckland, Sch Med, Dept Pharmacol & Clin Pharmacol, Auckland, New Zealand Univ Auckland Auckland New Zealand ol, Auckland, New Zealand
Citazione:
S.F. Zhou et al., "Effects of anticancer drugs on the metabolism of the anticancer drug 5,6-dimethylxanthenone-4-acetic (DMXAA) by human liver microsomes", BR J CL PH, 52(2), 2001, pp. 129-136

Abstract

Aims To investigate the effects of various anticancer drugs on the major metabolic pathways (glucuronidation and 6-methylhydroxylation) of DMXAA in human liver microsomes. Methods The effects of various anticancer drugs at 100 and 500 mum on the formation of DMXAA acyl glucuronide (DMXAA-G) and 6-hydroxymethyl-5-methylxanthenone-4-acetic acid (6-OH-MXAA) in human liver microsomes were determined by high performance liquid chromatography (h.p.l.c.). For those anticancer drugs showing significant inhibition of DMXAA metabolism, the inhibitionconstants (K-i) were determined. The resulting in vitro data were extrapolated to predict in vivo changes in DMXAA pharmacokinetics. Results Vinblastine, vincristine and amsacrine at 500 mum significantly (P< 0.05) inhibited DMXAA glucuronidation (K-i = 319, 350 and 230 mum, respectively), but not 6-methylhydroxylation in human liver microsomes. Daunorubicin and N-[2-(dimethylamino)-ethyl]acridine-4-carboxamide (DACA) at 100 and 500 mum showed significant (P < 0.05) inhibition of DMXAA 6-methylhydroxylation (K-i = 131 and 0.59 mum, respectively), but not glucuronidation. Other drugs such as 5-fluoroucacil, paclitaxel, tirapazamine and methotrexate exhibited little or negligible inhibition of the metabolism of DMXAA. Pre-incubation of microsomes with the anticancer drugs (100 and 500 mum) did notenhance their inhibitory effects on DMXAA metabolism. Prediction of DMXAA-drug interactions in vivo based on these in vitro data indicated that all the anticancer drugs investigated except DACA appear unlikely to alter the pharmacokinetics of DMXAA, whereas DACA may increase the plasma AUC of DMXAAby 6%. Conclusions These results indicate that alteration of the pharmacokineticsof DMXAA appears unlikely when used in combination with other common anticancer drugs. However, this does not rule out the possibility of pharmacokinetic interactions with other drugs used concurrently with this combination of anticancer drugs.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 16/07/20 alle ore 05:46:32