title: Phase I clinical trial of the flavonoid quercetin: pharmacokinetics and evidence for in vivo tyrosine kinase inhibition.
abstract: We have performed a Phase I clinical trial with the naturally occurring flavonoid quercetin (3,3',4',5,7-pentahydroxyflavone). Quercetin has antiproliferative activity in vitro and is known to inhibit signal transduction targets including tyrosine kinases, protein kinase C, and phosphatidyl inositol-3 kinase. Quercetin was administered by short i.v. infusion at escalating doses initially at 3-week intervals. The first dose level was 60 mg/m2; at the 10th dose level of 1700 mg/m2, dose-limiting nephrotoxicity was encountered, but no myelosuppression. At the preceding dose level of 1400 mg/m2, five patients were treated at 3-week intervals, and another eight patients were treated on a once-weekly schedule; overall, 2 of 10 evaluable patients had renal toxicity, 1 at grade 2 and 1 at grade 4. We therefore treated other patients at 945 mg/m2 (eight at 3-week intervals and six at weekly intervals); 3 of 14 patients had clinically significant renal toxicity, 2 patients with grade 2 and 1 patient with grade 3. Patients treated on the weekly schedule did not have cumulative renal impairment but did have a fall in the glomerular filtration rate of 19 +/- 8% in the 24 h after drug administration. We recommend 1400 mg/m2 as the bolus dose, which may be given either in 3-week or weekly intervals, for Phase II trials. Quercetin pharmacokinetics were described by a first-order two-compartment model with a median t(1/2)alpha of 6 min and median t(1/2)beta of 43 min. The median estimated clearance was 0.28 liter/min/m2, and median volume of distribution at steady state was 3.7 liter/m2. In 9 of 11 patients, lymphocyte protein tyrosine phosphorylation was inhibited following administration of quercetin at 1 h, which persisted to 16 h. In one patient with ovarian cancer refractory to cisplatin, following two courses of quercetin (420 mg/m2), the CA 125 had fallen from 295 to 55 units/ml, and in another patient with hepatoma, the serum alpha-fetoprotein fell. In conclusion, quercetin can be safely administered by i.v. bolus at a dose injection. The plasma levels achieved inhibited lymphocyte tyrosine kinase activity, and evidence of antitumor activity was seen.
authors.affiliation: Cancer Research Campaign Institute for Cancer Studies, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, United Kingdom.
authors.forename: D R
authors.initials: DR
authors.lastname: Ferry
authors.forename: A
authors.initials: A
authors.lastname: Smith
authors.forename: J
authors.initials: J
authors.lastname: Malkhandi
authors.forename: D W
authors.initials: DW
authors.lastname: Fyfe
authors.forename: P G
authors.initials: PG
authors.lastname: deTakats
authors.forename: D
authors.initials: D
authors.lastname: Anderson
authors.forename: J
authors.initials: J
authors.lastname: Baker
authors.forename: D J
authors.initials: DJ
authors.lastname: Kerr
mesh_terms: D000328:Adult; D000368:Aged; D004791:Enzyme Inhibitors / Q000009:adverse effects*; D005260:Female; D006801:Humans; D007668:Kidney / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011188:Potassium / Q000097:blood; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011794:Quercetin / Q000009:adverse effects* / Q000493:pharmacokinetics
chemical_list: D004791:Enzyme Inhibitors; D011794:Quercetin; D011505:Protein-Tyrosine Kinases; D011188:Potassium