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Titolo:
The P-glycoprotein antagonist PSC 833 increases the plasma concentrations of 6 alpha-hydroxypaclitaxel, a major metabolite of paclitaxel
Autore:
Kang, MH; Figg, WD; Ando, Y; Blagosklonny, MV; Liewehr, D; Fojo, T; Bates, SE;
Indirizzi:
NCI, Med Branch, NIH, Bethesda, MD 20892 USA NCI Bethesda MD USA 20892NCI, Med Branch, NIH, Bethesda, MD 20892 USA NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA NCI Bethesda MD USA 20892 ta Management Sect, NIH, Bethesda, MD 20892 USA NCI, Div Clin Sci, NIH, Bethesda, MD 20892 USA NCI Bethesda MD USA 20892NCI, Div Clin Sci, NIH, Bethesda, MD 20892 USA
Titolo Testata:
CLINICAL CANCER RESEARCH
fascicolo: 6, volume: 7, anno: 2001,
pagine: 1610 - 1617
SICI:
1078-0432(200106)7:6<1610:TPAP8I>2.0.ZU;2-M
Fonte:
ISI
Lingua:
ENG
Soggetto:
RESISTANCE GENE-PRODUCT; HUMAN LIVER-MICROSOMES; MULTIDRUG-RESISTANCE; CYTOCHROME-P450 3A4; BIOLOGICAL-ACTIVITY; DRUG-INTERACTIONS; TAXOL METABOLISM; CYCLOSPORINE-A; PHASE-II; EXPRESSION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Citazioni:
39
Recensione:
Indirizzi per estratti:
Indirizzo: Figg, WD NCI, Med Branch, NIH, Bldg 10,Room 5A01,9000 Rockville Pike, Bethesda, MD 20892 USA NCI Bldg 10,Room 5A01,9000 Rockville Pike Bethesda MD USA 20892 A
Citazione:
M.H. Kang et al., "The P-glycoprotein antagonist PSC 833 increases the plasma concentrations of 6 alpha-hydroxypaclitaxel, a major metabolite of paclitaxel", CLIN CANC R, 7(6), 2001, pp. 1610-1617

Abstract

Purpose: Overexpression of P-glycoprotein (Pgp) is one mechanism of drug resistance in cancer chemotherapy, A Phase I trial was conducted using PSC 833, a Pgp antagonist, in combination with paclitaxel in patients with refractory cancer. The objective of this study was to assess the effect of PSC 833 on the metabolism of paclitaxel and characterize the differences in 6 alpha -hydroxypaclitaxel pharmacokinetics. In addition, we examined the possibility of enhanced cytotoxicity of paclitaxel by the coexistence of 6 alpha-hydroxypaclitaxel. Experimental Design: Patients received paclitaxel 35 mg/m(2)/day by continuous intravenous infusion (CIVI) x 4 days without PSC 833 in cycle I and escalating doses of paclitaxel (13.1, 17.5, or 21.3 mg/m(2)/day CIVI x 4 days) with 5 mg/kg PSC 833 by mouth every 6 h x 7 days in cycle 2. Plasma samples were analyzed for both paclitaxel and its major metabolite with high-performance liquid chromatography methods. Using human liver microsomes, we studied the effect of PSC 833 on the metabolism of paclitaxel, In addition, the in vitro cytotoxicity of 6 alpha -hydroxypaclitaxel alone and in combination with paclitaxel was evaluated,Results,, Twenty-one of 22 patients had a metabolite peak (6 alpha -hydroxypaclitaxel) observed in the chromatogram of plasma samples from cycle 2 when they received paclitaxel in combination with PSC 833, This metabolite was not detectable in plasma obtained during the first cycle when they received paclitaxel without PSC 833, During cycle 2, the mean concentrations of 6alpha -hydroxypaclitaxel and paclitaxel were 0.10 +/- 0.074 and 0.079 +/- 0.041 mug/ml, respectively. A moderate association was observed between total bilirubin and 6a-hydroxypaclitaxel concentrations (P = 0.015, r 0.52; n = 21), Human liver microsome experiments showed that a PSC 833 concentration as high as 10 phr did not affect the production of 6 alpha -hydroxypaclitaxel. Paclitaxel cytotoxicity in HL60 and K562 human leukemia cells was increased in the presence of noncytotoxic concentrations of 6 alpha -hydroxypaclitaxel. Conclusions: PSC 833 increases the plasma concentration of 6 alpha -hydroxypaclitaxel during paclitaxel therapy, Inhibition of cytochrome P-450 3A4 by PSC 833 may explain this in part, although other mechanisms cannot be excluded.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 23/01/20 alle ore 04:04:30