Phase I clinical trial of the flavonoid quercetin : pharmacokinetics and evidence for in vivo tyrosine kinase inhibition

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.

Medienart:	Artikel

Erscheinungsjahr:	1996
Erschienen:	1996

Enthalten in:	Zur Gesamtaufnahme - volume:2
Enthalten in:	Clinical cancer research : an official journal of the American Association for Cancer Research - 2(1996), 4 vom: 17. Apr., Seite 659-68

Sprache:	Englisch

Beteiligte Personen:	Ferry, D R [VerfasserIn] Smith, A [VerfasserIn] Malkhandi, J [VerfasserIn] Fyfe, D W [VerfasserIn] deTakats, P G [VerfasserIn] Anderson, D [VerfasserIn] Baker, J [VerfasserIn] Kerr, D J [VerfasserIn]

Themen:	9IKM0I5T1E Clinical Trial Clinical Trial, Phase I EC 2.7.10.1 Enzyme Inhibitors Journal Article Potassium Protein-Tyrosine Kinases Quercetin RWP5GA015D Research Support, Non-U.S. Gov't

Anmerkungen:	Date Completed 10.02.1999 Date Revised 18.03.2022 published: Print Citation Status MEDLINE

Förderinstitution / Projekttitel:

PPN (Katalog-ID):	NLM09754079X