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Pharmacokinetics, Pharmacodynamics, and PKPD Modeling of Curcumin in Regulating Antioxidant and Epigenetic Gene Expression in Healthy Human Volunteers.
Mol Pharm. 2019 05 06; 16(5):1881-1889.MP

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 suggest health benefits in many diseases due to its antioxidant/anti-inflammatory 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 acute pharmacokinetics and pharmacodynamics (PK/PD) of commercially marketed curcumin in normal, healthy human volunteers. Twelve volunteers received a 4 g dose of curcumin capsules with a standard breakfast. Plasma samples were collected at specified time points and analyzed for curcumin and its glucuronide levels. RNA was extracted from leukocytes and analyzed for expression of select antioxidant and epigenetic histone deacetylase (HDAC) genes. Plasma levels of parent curcumin were below the detection limit by HPLC-ITMS/MS/MS. However, curcumin-O-glucuronide (COG), a major metabolite of curcumin, was detected as soon as 30 min. These observations of little to no curcumin and some levels of metabolite are in line with previous studies. PD marker antioxidant genes NRF2, HO-1, and NQO1 and epigenetic genes HDAC1, HDAC2, HDAC3, and HDAC4 were quantified by qPCR. COG PK is well-described by a one-compartment model, and the PK/PD of COG and its effect on antioxidant and epigenetic gene expression are captured by an indirect response model (IDR). A structural population PK model was sequentially established using a nonlinear mixed-effect model program (Monolix Lixoft, Orsay, France). Physiologically based pharmacokinetic modeling (PBPK) and simulation using Simcyp correlated well with the observed data. Taken together, these results show that the bioavailability of the parent curcumin compound is low, and oral administration of curcumin can still deliver detectable levels of curcumin glucuronide metabolite. But most importantly, it elicits antioxidant and epigenetic effects which could contribute to the overall health beneficial effects of curcumin.

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Authors+Show Affiliations

Cheng D
Department of Pharmaceutics, Ernest Mario School of Pharmacy , Rutgers, The State University of New Jersey , Piscataway , New Jersey 08854 , United States. Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy , Rutgers, The State University of New Jersey , Piscataway , New Jersey 08854 , United States.
Li W
Department of Pharmaceutics, Ernest Mario School of Pharmacy , Rutgers, The State University of New Jersey , Piscataway , New Jersey 08854 , United States. Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases , Institute of Translational Medicine, Medical College, Yangzhou University , Yangzhou 225001 , PR China.
Wang L
Department of Pharmaceutics, Ernest Mario School of Pharmacy , Rutgers, The State University of New Jersey , Piscataway , New Jersey 08854 , United States. Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy , Rutgers, The State University of New Jersey , Piscataway , New Jersey 08854 , United States.
Lin T
Department of Pharmaceutics, Ernest Mario School of Pharmacy , Rutgers, The State University of New Jersey , Piscataway , New Jersey 08854 , United States.
Poiani G
Department of Medicine, Division of Pulmonary/Critical Care Medicine , Robert Wood Johnson Medical School , New Brunswick , New Jersey 08901 , United States. Robert Wood Johnson University Hospital Somerset , Somerville , New Jersey 08876 , United States.
Wassef A
Department of Pharmaceutics, Ernest Mario School of Pharmacy , Rutgers, The State University of New Jersey , Piscataway , New Jersey 08854 , United States.
Hudlikar R
Department of Pharmaceutics, Ernest Mario School of Pharmacy , Rutgers, The State University of New Jersey , Piscataway , New Jersey 08854 , United States.
Ondar P
Robert Wood Johnson University Hospital , New Brunswick , New Jersey 08901 , United States.
Brunetti L
Department of Pharmaceutics, Ernest Mario School of Pharmacy , Rutgers, The State University of New Jersey , Piscataway , New Jersey 08854 , United States. Robert Wood Johnson University Hospital Somerset , Somerville , New Jersey 08876 , United States. Department of Pharmacy Practice, Ernest Mario School of Pharmacy , Rutgers, The State University of New Jersey , Piscataway , New Jersey 08854 , United States.
Kong AN
Department of Pharmaceutics, Ernest Mario School of Pharmacy , Rutgers, The State University of New Jersey , Piscataway , New Jersey 08854 , United States.

MeSH

Administration, OralAdolescentAdultAntioxidantsBiological AvailabilityCapsulesCurcumaCurcuminEpigenesis, GeneticFemaleGene Expression RegulationGlucuronidesHealthy VolunteersHeme Oxygenase-1Histone DeacetylasesHumansMaleModels, BiologicalNAD(P)H Dehydrogenase (Quinone)NF-E2-Related Factor 2Plant ExtractsYoung Adult

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

30860383

Citation

Cheng, David, et al. "Pharmacokinetics, Pharmacodynamics, and PKPD Modeling of Curcumin in Regulating Antioxidant and Epigenetic Gene Expression in Healthy Human Volunteers." Molecular Pharmaceutics, vol. 16, no. 5, 2019, pp. 1881-1889.
Cheng D, Li W, Wang L, et al. Pharmacokinetics, Pharmacodynamics, and PKPD Modeling of Curcumin in Regulating Antioxidant and Epigenetic Gene Expression in Healthy Human Volunteers. Mol Pharm. 2019;16(5):1881-1889.
Cheng, D., Li, W., Wang, L., Lin, T., Poiani, G., Wassef, A., Hudlikar, R., Ondar, P., Brunetti, L., & Kong, A. N. (2019). Pharmacokinetics, Pharmacodynamics, and PKPD Modeling of Curcumin in Regulating Antioxidant and Epigenetic Gene Expression in Healthy Human Volunteers. Molecular Pharmaceutics, 16(5), 1881-1889. https://doi.org/10.1021/acs.molpharmaceut.8b01246
Cheng D, et al. Pharmacokinetics, Pharmacodynamics, and PKPD Modeling of Curcumin in Regulating Antioxidant and Epigenetic Gene Expression in Healthy Human Volunteers. Mol Pharm. 2019 05 6;16(5):1881-1889. PubMed PMID: 30860383.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacokinetics, Pharmacodynamics, and PKPD Modeling of Curcumin in Regulating Antioxidant and Epigenetic Gene Expression in Healthy Human Volunteers. AU - Cheng,David, AU - Li,Wenji, AU - Wang,Lujing, AU - Lin,Tiffany, AU - Poiani,George, AU - Wassef,Andrew, AU - Hudlikar,Rasika, AU - Ondar,Patricia, AU - Brunetti,Luigi, AU - Kong,Ah-Ng, Y1 - 2019/03/28/ PY - 2019/3/13/pubmed PY - 2020/2/27/medline PY - 2019/3/13/entrez KW - NRF2 KW - curcumin KW - inflammation KW - oxidative stress KW - pharmacokinetics/pharmacodynamics SP - 1881 EP - 1889 JF - Molecular pharmaceutics JO - Mol Pharm VL - 16 IS - 5 N2 - 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 suggest health benefits in many diseases due to its antioxidant/anti-inflammatory 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 acute pharmacokinetics and pharmacodynamics (PK/PD) of commercially marketed curcumin in normal, healthy human volunteers. Twelve volunteers received a 4 g dose of curcumin capsules with a standard breakfast. Plasma samples were collected at specified time points and analyzed for curcumin and its glucuronide levels. RNA was extracted from leukocytes and analyzed for expression of select antioxidant and epigenetic histone deacetylase (HDAC) genes. Plasma levels of parent curcumin were below the detection limit by HPLC-ITMS/MS/MS. However, curcumin-O-glucuronide (COG), a major metabolite of curcumin, was detected as soon as 30 min. These observations of little to no curcumin and some levels of metabolite are in line with previous studies. PD marker antioxidant genes NRF2, HO-1, and NQO1 and epigenetic genes HDAC1, HDAC2, HDAC3, and HDAC4 were quantified by qPCR. COG PK is well-described by a one-compartment model, and the PK/PD of COG and its effect on antioxidant and epigenetic gene expression are captured by an indirect response model (IDR). A structural population PK model was sequentially established using a nonlinear mixed-effect model program (Monolix Lixoft, Orsay, France). Physiologically based pharmacokinetic modeling (PBPK) and simulation using Simcyp correlated well with the observed data. Taken together, these results show that the bioavailability of the parent curcumin compound is low, and oral administration of curcumin can still deliver detectable levels of curcumin glucuronide metabolite. But most importantly, it elicits antioxidant and epigenetic effects which could contribute to the overall health beneficial effects of curcumin. SN - 1543-8392 UR - https://www.unboundmedicine.com/medline/citation/30860383/Pharmacokinetics_Pharmacodynamics_and_PKPD_Modeling_of_Curcumin_in_Regulating_Antioxidant_and_Epigenetic_Gene_Expression_in_Healthy_Human_Volunteers_ L2 - https://doi.org/10.1021/acs.molpharmaceut.8b01246 DB - PRIME DP - Unbound Medicine ER -