Subscriber access provided by Uppsala universitetsbibliotek
Article
Pharmacokinetics, pharmacodynamics and PKPD modeling of curcumin in regulating antioxidant and epigenetic gene expression in human healthy volunteers David Cheng, Wenji Li, Lujing Wang, Tiffany Lin, George Poiani, Andrew Wassef, Rasika Hudlikar, Patricia Ondar, Luigi Brunetti, and Ah-Ng Kong Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.8b01246 • Publication Date (Web): 12 Mar 2019 Downloaded from http://pubs.acs.org on March 16, 2019
Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.
Page 1 of 31 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Molecular Pharmaceutics
88x35mm (300 x 300 DPI)
ACS Paragon Plus Environment
Molecular Pharmaceutics 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
1
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
Pharmacokinetics, pharmacodynamics and PKPD modeling of curcumin in regulating antioxidant and epigenetic gene expression in human healthy volunteers David Chenga,b,1, Wenji Lia,c,1, Lujing Wanga,b,1, Tiffany Lin a, George Poianid, Andrew Wassef a, Rasika Hudlikara, Patricia Ondare, Luigi Brunettia,f and Ah-Ng Konga,* a Department
of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA b Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA c Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, PR China; Jiangsu Key laboratory of integrated traditional Chinese and Western Medicine for prevention and treatment of Senile Diseases, Yangzhou University, Yangzhou, 225001, PR China d Department of Medicine, Robert Wood Johnson University Hospital-Somerset, NJ and Division of Pulmonary/Critical Care Medicine, Robert Wood Johnson Medical School, New Brunswick, NJ. e Robert Wood Johnson University Hospital, New Brunswick, NJ. f Department of Pharmacy Practice, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA. 1Equal
contribution
*Correspondence should be addressed to: Professor Ah-Ng Tony Kong Rutgers, The State University of New Jersey Ernest Mario School of Pharmacy, Room 228 160 Frelinghuysen Road, Piscataway, NJ 08854, USA Email:
[email protected] Phone: 848-445-6369/8 Fax: 732-445-3134 Running title: PKPD of curcumin in human healthy subjects
37
ACS Paragon Plus Environment
Page 2 of 31
Page 3 of 31 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Molecular Pharmaceutics 2
1
Abstract
2
Curcumin is a major component of the spice, turmeric (Curcuma longa) often used
3
in food or as a dietary supplement. Many preclinical studies on curcumin suggest health
4
benefit in many diseases due to its antioxidant/anti-inflammatory and epigenetic effects.
5
The few human studies and curcumin’s unfavorable pharmacokinetics (PK) have
6
limited its potential, leading researchers to study and develop formulations to improve
7
its PK. The purpose of this clinical study is to describe the acute pharmacokinetics and
8
pharmacodynamics (PK/PD) of commercially marketed curcumin in normal, healthy
9
human volunteers. Twelve volunteers received 4 g dose of curcumin capsules with
10
standard breakfast. Plasma samples were collected at specified time points and analyzed
11
for curcumin and its glucuronide levels. RNA was extracted from leukocytes and
12
analyzed for expression of select antioxidant and epigenetic histone deacetylase
13
(HDAC) genes. Plasma levels of parent curcumin were below the detection limit by
14
HPLC-ITMS/MS/MS. However, curcumin-O-glucuronide (COG), a major metabolite
15
of curcumin, was detected as soon as 30 min. These observations of little to no curcumin
16
and some levels of metabolite are in line with previous studies. PD markers antioxidant
17
genes NRF2, HO-1, NQO1, and epigenetic genes HDAC1, HDAC2, HDAC3, and
18
HDAC4 were quantified by qPCR. COG PK are well-described by a one-compartment
19
model and the PK/PD of COG and its effect on antioxidant and epigenetic gene
20
expression are captured by indirect response model (IDR). A structural population PK
21
model was sequentially established using the nonlinear mixed-effect model program
22
(Monolix Lixoft, Orsay, France). Physiologically based pharmacokinetic modeling
23
(PBPK) and simulation using Simcyp correlated well with the observed data. Taken
24
together these results show that the bioavailability of the parent curcumin compound is
25
low, and oral administration of curcumin can still deliver detectable levels of curcumin
26
glucuronide metabolite. But most importantly, it elicits antioxidant and epigenetic
27
effects which could contribute to the overall health beneficial effects of curcumin.
28 29
Keywords: Curcumin; pharmacokinetics/pharmacodynamics; NRF2; oxidative stress,
ACS Paragon Plus Environment
Molecular Pharmaceutics 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
3
1
inflammation
ACS Paragon Plus Environment
Page 4 of 31
Page 5 of 31 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Molecular Pharmaceutics 4
1
Introduction
2
Curcumin, a natural polyphenol, is the major component of rhizomes from the spice,
3
turmeric (Curcuma longa) often used in food and in traditional Ayurvedic medicine.
4
Many studies have investigated the therapeutic potential of curcumin across many
5
diseases such as cancer, diabetes, osteoarthritis, and antianxiety 1. Curcumin’s reported
6
benefits and its safety at even high doses of up to 12g/day
7
popular health supplement
8
supplement in natural retail stores in United States with sales reaching $47,654,008 and
9
analysis of Google search queries shows spike in interest, classifying curcumin as a
10
“breakout star” 3. Therefore, its growing popularity has drawn researchers to investigate
11
its mechanisms and potential.
1.
2
has made curcumin a
In 2016, curcumin remained the top-selling herbal
12
The wide range of curcumin’s pharmacological activity is due to its observed
13
pleotropic activities 4. Although there appear to be countless benefits of curcumin
14
supplementation, the majority of these benefits can be attributed to its antioxidant and
15
anti-inflammatory effects 5. Curcumin’s antioxidant activity is due in part to its
16
modulation of nuclear factor (erythroid-derived 2)-like 2 (NRF2), an important
17
regulator of cellular response to oxidative stress 6 that activates downstream antioxidant
18
genes such as heme oxygenase-1 (HO-1)
19
(NQO1) 9 and glutathione S-transferase P1 (GSTP1) 10. Knockout of NRF2 attenuates
20
curcumin’s antioxidant activity in mouse macrophages
21
effects have also been reported in neuroprotection
22
chronic kidney disease 15. Curcumin’s ability to suppress inflammation have also been
23
widely reported 16. In human tenocytes stimulated with IL-1β, curcumin downregulated
24
NF-κB
25
metalloproteinase-1, -9, and -13 gene expression
26
oxide synthase (NOS) induction and nitric oxide production in lipopolysaccharide
27
(LPS) and interferon-γ stimulated RAW 264.7 macrophages 18.
28 29
signaling
and
decreased
7, 8,
NAD(P)H dehydrogenase [quinone] 1
11
12,
cancer prevention
cyclooxygenase-2 17.
and curcumin’s antioxidant
production
13, 14,
and
and
matrix
Curcumin can also inhibit nitric
Recent investigations have revealed that curcumin may exhibit epigenetic modifying effects
19, 20.
Curcumin exerts effects on multiple epigenetic regulators such as DNA
ACS Paragon Plus Environment
Molecular Pharmaceutics 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Page 6 of 31
5
1
methyltransferases
2
acetyltransferases (HATs), and micro RNAs (miRNAs) 13. Curcumin has been shown
3
to inhibit HDAC expression and increase Ac-histone H4 in Raji cells 21. In colorectal
4
cancer cells, curcumin shows anti-cancer activity in part by modulating and
5
demethylating CpG loci of certain genes 22. Additional studies have revealed curcumin
6
can inhibit DNMTs and HDACs to restore gene expression of NRF2
7
and DLEC1
8
colon cancer mouse model, DNA methylation of Tnf was discovered to be
9
hypermethylated in mice fed with curcumin compared to AOM-DSS alone, providing
10
further evidence of curcumin’s chemopreventive effects, possibly via epigenetic
11
mechanisms 26.
25.
(DNMTs),
histone
deacetylases
(HDACs),
23,
histone
Neurog1 24,
Recently, in an azoxymethane-dextran sulfate sodium (AOM-DSS)
12
Due to curcumin’s reported antioxidant and anti-inflammatory effects and
13
widespread use as a supplement, several clinical trials have characterized its
14
pharmacokinetic (PK) and pharmacodynamic (PD) profile and curcumin’s potential use
15
in humans across a wide range of disease states 27. However, curcumin possesses poor
16
oral bioavailability both in human and in preclinical models due to its poor absorption,
17
fast metabolism and elimination 28. To address these challenges, various formulations
18
of curcumin have been developed and tested. One method has been to use piperine, a
19
major component of black pepper, and combining it with curcumin to inhibit
20
metabolism by UDP-glucuronosyl transferase (UGTs) and thus enhance curcumin’s
21
bioavailability
22
bioavailability and on investigating its effects in disease, to date, few studies have
23
matched PK and PD of commercially marketed curcumin and no studies have been
24
done to study the PK/PD of curcumin on antioxidant and epigenetic gene activity. Our
25
current study aims to describe the effects of oral curcumin on the antioxidant and
26
epigenetic modifiers in healthy human volunteers using a PK/PD modeling approach.
27
Materials and Methods
28
Subjects
29, 30.
While many studies on curcumin have focused on improving
ACS Paragon Plus Environment
Page 7 of 31 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Molecular Pharmaceutics 6
1
Twelve healthy volunteers aged 18-27 years (seven men and five women) were
2
recruited into the study following approval from the Rutgers University institutional
3
review board (protocol ID 20160000736). Subjects aged 18 to 65 years of age with a
4
body mass index between 18.0 - 29.9 kg/m2 were eligible for inclusion. The subjects
5
agreed to avoid curcumin 14 days prior to arriving at study site. A standardized
6
breakfast with 750 calories and 35 g of fat was provided to delay gastric emptying
7
and help enhance curcumin absorption. All volunteer samples were collected at Robert
8
Wood Johnson University Hospital-Somerset. Exclusion criteria included allergy to
9
curcumin or black pepper, history of malignancy, autoimmune disease, pancreatic or
10
biliary tract disease, renal or hepatic disease, or diagnosis of anemia (hemoglobin
