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,