Enhancement of curcumin oral absorption and pharmacokinetics of curcuminoids and curcumin metabolites in mice

Abstract

Purpose: Curcumin has shown a variety of biological activity for various human diseases including cancer in preclinical setting. Its poor oral bioavailability poses significant pharmacological barriers to its clinical application. Here, we established a practical nano-emulsion curcumin (NEC) containing up to 20% curcumin (w/w) and conducted the pharmacokinetics of curcuminoids and curcumin metabolites in mice.

Methods: This high loading NEC was formulated based on the high solubility of curcumin in polyethylene glycols (PEGs) and the synergistic enhancement of curcumin absorption by PEGs and Cremophor EL. The pharmacokinetics of curcuminoids and curcumin metabolites was characterized in mice using a LC-MS/MS method, and the pharmacokinetic parameters were determined using WinNonlin computer software.

Results: A tenfold increase in the AUC (0→24h) and more than 40-fold increase in the C (max) in mice were observed after an oral dose of NEC compared with suspension curcumin in 1% methylcellulose. The plasma pharmacokinetics of its two natural congeners, demethoxycurcumin and bisdemethoxycurcumin, and three metabolites, tetrahydrocurcumin (THC), curcumin-O-glucuronide, and curcumin-O-sulfate, was characterized for the first time in mice after an oral dose of NEC.

Conclusion: This oral absorption enhanced NEC may provide a practical formulation to conduct the correlative study of the PK of curcuminoids and their pharmacodynamics, e.g., hypomethylation activity in vivo.

Fig. 1

The tautomerized structures of three natural curcuminoids: curcumin, demethoxycurcumin, and bisdemethoxycurcumin

Fig. 2

Plasma concentration 1-h post-oral administration of several NECs and SC after single dose administration (1,000 mg/kg; n = 2) a and the stability of formulation F7 for 60 days b

Fig. 3

The solubility of VEH (vehicle), NEC and CUR in water and the NEC particle in water (0.26 mg/ml) measured by transmission electron microscope (TEM) image size

Fig. 4

Plasma concentration–time profile following single oral administration of NEC and SC after single dose administration (1,800 mg/kg; n = 6), pink SC, and blue NEC

Fig. 5

Representative LC–MS/MS chromatograms of extracts of plasma from mouse, which had received NEC at 1,800 mg/kg by oral gavage, demonstrating multiple reaction monitoring transitions indicative of curcumin a, demethoxycurcumin b, bisdemethoxycurcumin c, tetrahydrocurcumin d, curcumin-O-monoglucuronide e, curcumin-O-monosulfate f, plasmas were obtained 20 min after gel curcumin administration. For details of administration and LC-MS analysis see “Materials and methods”

Fig. 6

Plasma concentration-time profile of curcumin, demethoxycurcumin, bisdemethoxycurcumin, tetrahydrocurcumin, curcumin-O-glucuronide, and curcumin-O-sulfate following single oral administration of after a single dose administration of NEC containing 860 mg/kg curcumin, 100 mg/kg demethoxycurcumin, and 40 mg/kg bisdemethoxycurcumin (n = 3)