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Pre-clinical and clinical study of QC12, a water-soluble, pro-drug of quercetin
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Mulholland, P. J., Ferry, D. R., Anderson, D., Hussain, S. A., Young, Annie M., Cook, J. E., Hodgkin, E., Seymour, L. W. and Kerr, D. J. (2001) Pre-clinical and clinical study of QC12, a water-soluble, pro-drug of quercetin. Annals of Oncology, 12 (2). pp. 245-248. doi:10.1023/A:1008372017097
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Official URL: http://dx.doi.org/10.1023/A:1008372017097
Abstract
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 μMolar (μM). A two-compartment model with mean t1/2α of 0.31 ± 0.27 hours and mean t1/2β of 0.86 ± 0.78 hours best described the concentration-time curves for QC12. The mean AUC was 44.54 ± 13.0 μM. 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 μM. 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.
| Item Type: | Journal Article | ||||
|---|---|---|---|---|---|
| Subjects: | R Medicine > R Medicine (General) | ||||
| Divisions: | Faculty of Medicine > Warwick Medical School > Health Sciences > Clinical Trials Unit Faculty of Medicine > Warwick Medical School > Health Sciences Faculty of Medicine > Warwick Medical School |
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| Journal or Publication Title: | Annals of Oncology | ||||
| Publisher: | Oxford University Press | ||||
| ISSN: | 0923-7534 | ||||
| Official Date: | 1 February 2001 | ||||
| Dates: |
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| Volume: | 12 | ||||
| Number: | 2 | ||||
| Page Range: | pp. 245-248 | ||||
| DOI: | 10.1023/A:1008372017097 | ||||
| Status: | Peer Reviewed | ||||
| Publication Status: | Published | ||||
| Access rights to Published version: | Restricted or Subscription Access |
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