Pre-clinical and clinical study of QC12, a water-soluble, pro-drug of quercetin

Citation
Pj. Mulholland et al., Pre-clinical and clinical study of QC12, a water-soluble, pro-drug of quercetin, ANN ONCOL, 12(2), 2001, pp. 245-248
Citations number
10
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
ANNALS OF ONCOLOGY
ISSN journal
0923-7534 → ACNP
Volume
12
Issue
2
Year of publication
2001
Pages
245 - 248
Database
ISI
SICI code
0923-7534(200102)12:2<245:PACSOQ>2.0.ZU;2-V
Abstract
Background: Quercetin is a naturally occurring flavonoid with many biologic al 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/m(2) three weekly, but the vehicle, dimethyl sulphoxide (DM SO) is unsuitable for further clinical development of quercetin. Patients and methods: A water-soluble, pro-drug of quercetin (3'(N-carboxym ethyl)carbomyl-3,4',5,7-tetrahydroxyflavone), QC12 has been synthesised. Si x cancer patients received 400 mg of QC12 (equivalent to 298 mg of querceti n), 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 QC1 2 or quercetin in plasma. After i.v. administration, we detected peak plasm a concentrations of QC12 of 108.7 +/- 41.67 mu Molar (muM). A two-compartme nt 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 QC 12. The mean AUC was 44.54 +/- 13.0 muM.hour and mean volume of distributio n (Vd) of 10.0 +/- 6.2 litres (l). Quercetin was found in all patients foll owing i.v. infusion of QC12, with peak levels of quercetin 19.9 +/- 11.8 mu M. The relative bioavailability of quercetin was estimated to be 20%-25% qu ercetin released from QC12. Conclusions: QC12 is not orally bioavailable. This water-soluble pro-drug w arrants further clinical investigation; starting with a formal phase I, IV, dose-escalation study.