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 occurrin g flavonoid quercetin (3,3',4',5,7-pentahydroxyflavone), Quercetin has antiproliferative activity in vitro and is known to inhibit signal tr ansduction targets including tyrosine kinases, protein kinase C, and p hosphatidyl inositol-3 kinase, Quercetin was administered by short i.v . infusion at escalating doses initially at 3-week intervals, The firs t dose level was 60 mg/m(2); at the 10th dose level of 1700 mg/m(2), d ose-limiting nephrotoxicity was encountered, but no myelosuppression. At the preceding dose level of 1400 mg/m(2), five patients were treate d at 3-week intervals, and another eight patients were treated on a on ce-weekly schedule; overall, 2 of 10 evaluable patients had renal toxi city, 1 at grade 2 and 1 at grade 4, We therefore treated other patien ts at 945 mg/m(2) (eight at 3-week intervals and six at weekly interva ls); 3 of 14 patients had clinically significant renal toxicity, 2 pat ients 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 aft er drug administration, We recommend 1400 mg/m(2) as the bolus dose, w hich may be given either in 3-week or weekly intervals, for Phase Il t rials. Quercetin pharmacokinetics were described by a first-order two- compartment model with a median t1/2 alpha of 6 min and median t1/2 be ta of 43 min, The median estimated clearance was 0.28 liter/min/m(2), and median volume of distribution at steady state was 3.7 liter/m(2), In 9 of 11 patients, lymphocyte protein tyrosine phosphorylation was i nhibited 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/m(2)), the CA 125 had falle n from 295 to 55 units/ml, and in another patient with hepatoma, the s erum alpha-fetoprotein fell, In conclusion, quercetin can be safely ad ministered by i.v. bolus at a dose injection. The plasma levels achiev ed inhibited lymphocyte tyrosine kinase activity, and evidence of anti tumor activity was seen.