Infusion Pharmacokinetics of Lipocurc™ (Liposomal Curcumin) and its Metabolite Tetrahydrocurcumin in Beagle Dogs

Curcumin's instability and its metabolite, tetrahydrocurcumin (THC) pose a major issue for the establishment of dependable pharmacokinetics and excretion profiles. Additional pharmacokinetic variances are associated with durations of intravenous infusions. We found that stabilizing curcumin with phosphoric acid allows accurate quantitative determinations of curcuminoids in the plasma and bile, by preventing degradation during the analytical processes. Two male and two females dogs were infused with Lipocurc™ 10 mg/kg over two hours, and another four dogs (two males and two females) were infused with Lipocurc™ 10 mg/kg over eight hours. Plasma levels of curcumin and THC were determined during the infusions and at necropsy. THC levels were 6.3-9.6- fold higher than curcumin during both infusion rates, suggesting a combination of a high-rate of enzymatic curcumin metabolism and a comparatively slower rate of blood THC clearance. When levels of curcumin and THC were compared during infusion durations, the two-hour infusion levels were significantly higher than the eight-hour infusion. The plasma half-lives of both compounds following the two-hour infusion ranged from 0.4-0.7 hours, and was a consequence of both hepatic and renal clearance However, at higher plasma concentrations renal excretion predominated, particularly with THC. Enhanced clearance rates were noted during eight-hour infusions, which prevented achieving a steady state. These observations suggest that for leukemias and lymphomas, the two-hour infusion may be advantageous based upon higher concentration profiles, and unstimulated clearance rates, however data on curcumin penetration into circulating hematopoietic cancer cells and efficacy data are required in order to confirm these suggestions. The parenteral administration of Lipocurc™ with therapeutic, intent poses several questions relating to deciding an optimal rate of administration for patients with neoplastic diseases. Options ranging from bolus intravenous injections to constant infusions are impacted by enzymatic metabolism, pH- dependent degradation, renal and hepato-biliary excretion mechanisms. During pre-clinical toxicological evaluation in dogs, dose-dependent hemolysis was noted following brief infusions of 20 mg/kg and greater curcumin content. Ten mg/kg doses infused over 2 hours were non-toxic. This same two-hour infusion schedule was used in an ascending-dose Phase 1 trial in normal human subjects where the highest intravenous dose administered (5 mg/kg) was without adverse reaction. In planning a clinical cancer trial with parenteral Lipocurc™ the most efficient administration schedule will be a function of multiple pharmacological and cellular attributes. The only modality capable of modulation is the dose and schedule of administration. To avoid toxicity from a too-high C max we designed a two-hour infusion schedule, however in view of the unknown metabolic and elimination factors in dogs we compared two-hour and four-fold longer infusions (eight hours) to determine any advantages.