The proposed mechanisms of action for the chemopreventive efficacy of curcumin are unknown but are thought to be via inhibition of arachidonate pathways and other mechanisms of cellular proliferative control. The overall objectives of the phase I trial are to describe the safety and pharmacokinetics of single and multiple doses of synthetic, micronized curcumin and to define the optimal three month dose and steady state pharmacokinetics with suppression of arachidonic acid metabolism in the colonic mucosa. In the first step of the trial (UMCC 9715), the pharmacokinetics and safety of single doses of curcumin in two formulations (Cyclox) labeled as dietary supplements will be compared: citrus-flavored dry packets for mixing in water and pure curcumin in gelatin capsules. Eligible participants are male and female volunteers 18 years of age with normal organ function and without high risk for colon cancer(i.e. familial syndrome, 2 first-degree relative with colon cancer, previous resected colon adenomatous polyp, colon ademoma with CIS or Dukes's A-C cancer). Six subjects entered at each dose level (50, 100. 200mg); one half (3/6) will receive each of the two formulations, with cross-over to the alternate formulation after a two-week wash-out. After taking the single dose with a standardized fatty meal, blood specimens will be obtained for pharmacokinetics at 0.5, 1, 2, 4, 6, 8, 12, 24, 32, 48, 72, and 96 hours. Urine will be collected for 24 hours. Pharmacokinetic endpoints for curcumin and two metabolites include AUC, tmax, CI, Ud, t1/2, and Ke. If grade 3 or greater drug related toxicity occurs in 1 subject, escalations will cease and the study closed. If Grade 2 or less drug related toxicity occurs in two or more of six subjects at a given dose level, escalations will cease and the study closed. If Grade 1 drug related toxicity occurs in two or more of six subjects at a given dose level, sugjects will be added at the next dose level. Decisions on the dose to be pursued in the multidose portion of this research will be made based on single -dose pharmacokinetics and safety.
NIH ExPorter
NIH ExPorter