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BACKGROUND: Quercetin is a naturally occurring flavonoid with many biological activities including inhibition of a number of tyrosine kinases. A phase I, dose-escalation trial of quercetin defined the maximum tolerated dose (MTD) as 1700 mg/m2 three weekly, but the vehicle, dimethyl sulphoxide (DMSO) is unsuitable for further clinical development of quercetin. PATIENTS AND METHODS: A water-soluble, pro-drug of quercetin (3'(N-carboxymethyl)carbomyl-3,4',5,7-tetrahydroxyflavone), QC12 has been synthesised. Six cancer patients received 400 mg of QC12 (equivalent to 298 mg of quercetin), orally on day 1 and intravenously (i.v.) in normal saline on day 14. RESULTS: Following oral administration of QC12 we were unable to detect QC12 or quercetin in plasma. After i.v. administration, we detected peak plasma concentrations of QC12 of 108.7 +/- 41.67 microMolar (microM). A two-compartment model with mean t(1/2)alpha of 0.31 +/- 0.27 hours and mean t(1/2)beta of 0.86 +/- 0.78 hours best described the concentration-time curves for QC12. The mean AUC was 44.54 +/- 13.0 microM.hour and mean volume of distribution (Vd) of 10.0 +/- 6.2 litres (l). Quercetin was found in all patients following i.v. infusion of QC12, with peak levels of quercetin 19.9 +/- 11.8 microM. The relative bioavailability of quercetin was estimated to be 20%-25% quercetin released from QC12. CONCLUSIONS: QC12 is not orally bioavailable. This water-soluble pro-drug warrants further clinical investigation; starting with a formal phase I, IV, dose-escalation study.

Original publication

DOI

10.1023/a:1008372017097

Type

Journal article

Journal

Ann Oncol

Publication Date

02/2001

Volume

12

Pages

245 - 248

Keywords

Adult, Aged, Biological Availability, Cell Survival, Chromatography, High Pressure Liquid, Drug Administration Routes, Drug Evaluation, Preclinical, Drug Stability, Female, Flavonoids, Humans, Male, Middle Aged, Neoplasms, Prodrugs, Tumor Cells, Cultured