Pharmacokinetics, Pharmacodynamics, and PKPD Modeling of Curcumin in Regulating Antioxidant and Epigenetic Gene Expression in Healthy Human Volunteers

Abstract

Curcumin is a major component of the spice, turmeric (Curcuma longa) often used in food or as a dietary supplement. Many preclinical studies on curcumin suggests benefit in many diseases due to its antioxidant and epigenetic effects. The few human studies and curcumin's unfavorable pharmacokinetics (PK) have limited its potential, leading researchers to study and develop formulations to improve its PK. The purpose of this clinical study is to describe the pharmacokinetics and pharmacodynamics (PK/PD) of commercially marketed curcumin in normal, healthy human volunteers. Twelve volunteers received 4 g of curcumin capsules with standard breakfast. Plasma samples were collected at specified timepoints and analyzed for curcumin levels. RNA was extracted and analyzed for expression of select antioxidant and epigenetic histone deacetylase (HDAC) genes. Plasma levels of parent curcumin were not detected by HPLC‐ITMS/MS/MS. However, curcumin glucuronide, a major metabolite of curcumin, was detected as soon as 30 min. These observations of little to no curcumin and low levels of metabolite are in line with previous studies. Antioxidant genes Nrf2, HO‐1, NQO1, and HDAC1, HDAC2, HDAC3, and HDAC4 were quantified by qPCR. Curcumin glucuronide pharmacokinetics are well‐described by a one‐compartment model and the PK/PD of curcumin glucuronide and its effect on antioxidant and epigenetic gene expression are explained by indirect response model (IDR). Increasing AUC or exposure to curcumin glucuronide was correlated with overall PD response. Physiologically based pharmacokinetic modeling (PBPK) and simulation using Simcyp correlated well with our observed data in the human volunteers. In vitro experiments on curcumin glucuronide in HepG2C8 cells also show that Nrf2‐ARE luciferase activity increases after 24‐hour treatment. These results show that poor bioavailability of curcumin remains a challenge but that oral administration of curcumin delivers detectable levels of curcumin glucuronide and may mediate the antioxidant and epigenetic effects of curcumin. Support or Funding Information Grant: This work was supported in part by institutional funds and R01AT007065 from the National Center for Complementary and Alternative Medicines (NCCAM) and the Office of Dietary Supplements (ODS). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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