Chirality influence of zaltoprofen towards UDP-glucuronosyltransferases (UGTs) inhibition potential

Article abstract of DOI:10.1002/chir.22436

Abstract Zaltoprofen (ZLT) is a nonsteroidal antiinflammation drug, and has been clinically employed to treat rheumatoid arthritis, osteoarthritis, and other chronic inflammatory pain conditions. The present study aims to investigate the chirality influence of zaltoprofen towards the inhibition potential towards UDP-glucuronosyltransferases (UGTs) isoforms. In vitro a recombinant UGT isoforms-catalyzed 4-methylumbelliferone (4-MU) glucuronidation incubation system was employed to investigate the inhibition of (R)-zaltoprofen and (S)-zaltoprofen towards UGT isoforms. The inhibition difference capability was observed for the inhibition of (R)-zaltoprofen and (S)-zaltoprofen towards UGT1A8 and UGT2B7, but not for other tested UGT isoforms. (R)-zaltoprofen exhibited noncompetitive inhibition towards UGT1A8 and competitive inhibition towards UGT2B7. The inhibition kinetic parameters were calculated to be 35.3 μM and 19.2 μM for UGT1A8 and UGT2B7. (R)-zaltoprofen and (S)-zaltoprofen exhibited a different inhibition type towards UGT1A7. Based on the reported maximum plasma concentration of (R)-zaltoprofen in vivo, a high drug-drug interaction between (R)-zaltoprofen and the drugs mainly undergoing UGT1A7, UGT1A8, and UGT2B7-catalyzed glucuronidation was indicated. Chirality 27:359-363, 2015.

Full text of DOI:10.1002/chir.22436

CHIRALITY 27:359–363 (2015)
Short Communication
Chirality Influence of Zaltoprofen Towards UDP-
Glucuronosyltransferases (UGTs) Inhibition Potential
1
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1
4
7
4
LIN JIA, CUIMIN HU, HAINA WANG, YONGZHE LIU, XIN LIU, * YAN-YAN ZHANG, WEI LI, LI-XUAN WANG,
1
,4,6
2,4
YUN-FENG CAO,
First Affiliated Hospital of Liaoning Medical University, Jinzhou, Liaoning, People’s Republic of China
Department of Toxicology, School of Public Health, Tianjin Medical University, Heping District, Tianjin, People’s Republic of China
AND ZHONG-ZE FANG
1
2
3
Tianjin Life Science Research Center and Department of Microbiology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin,
People’s Republic of China
4
6
Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences and First Affiliated Hospital of Liaoning
Medical University, Dalian, People’s Republic of China
5
College of Pharmaceutical Sciences, Shandong University, Jinan, People’s Republic of China
Key Laboratory of Contraceptives and Devices Research (NPFPC), Shanghai Engineer and Technology Research Center of Reproductive Health Drug
and Devices, Shanghai Institute of Planned Parenthood Research, Shanghai, People’s Republic of China
7
Yangzhou University, Yangzhou, China
ABSTRACT
Zaltoprofen (ZLT) is a nonsteroidal antiinflammation drug, and has been clini-
cally employed to treat rheumatoid arthritis, osteoarthritis, and other chronic inflammatory pain
conditions. The present study aims to investigate the chirality influence of zaltoprofen towards
the inhibition potential towards UDP-glucuronosyltransferases (UGTs) isoforms. In vitro a re-
combinant UGT isoforms-catalyzed 4-methylumbelliferone (4-MU) glucuronidation incubation
system was employed to investigate the inhibition of (R)-zaltoprofen and (S)-zaltoprofen towards
UGT isoforms. The inhibition difference capability was observed for the inhibition of (R)-zaltoprofen
and (S)-zaltoprofen towards UGT1A8 and UGT2B7, but not for other tested UGT isoforms.
(
R)-zaltoprofen exhibited noncompetitive inhibition towards UGT1A8 and competitive inhibi-
tion towards UGT2B7. The inhibition kinetic parameters were calculated to be 35.3 μM and
9.2 μM for UGT1A8 and UGT2B7. (R)-zaltoprofen and (S)-zaltoprofen exhibited a different
inhibition type towards UGT1A7. Based on the reported maximum plasma concentration of
R)-zaltoprofen in vivo, a high drug–drug interaction between (R)-zaltoprofen and the drugs
mainly undergoing UGT1A7, UGT1A8, and UGT2B7-catalyzed glucuronidation was indicated.
Chirality 27:359–363, 2015.
1
(
© 2015 Wiley Periodicals, Inc.
KEY WORDS: zaltoprofen; chirality; UDP-glucuronosyltransferases (UGTs); inhibition potential
INTRODUCTION
inhibition towards UGT isoforms, including UGT1A4, 1A6,
9
1
A8, 1A9, and 2B7. Indinavir inhibited UGT1A1-catalyzed
Chirality describes a molecule with a nonsuperimposeable
mirror image of itself, and the molecules with chirality are called
enantiomers. The enantiomers always exhibit different, even
glucuronidation of bilirubin, and resulted in the elevation of
unconjugated bilirubin in serum.10
1
Zaltoprofen (ZLT) is a nonsteroidal antiinflammation drug,
and has been clinically employed to treat rheumatoid arthri-
tis, osteoarthritis, and other chronic inflammatory pain condi-
tions.11 The influence of the chirality of ZLT towards the drug
efficiency has been reported. The results reported by Cho
et al. have shown that the enantiomers of ZLT exerted differ-
ent antiinflammation and analgesic effects.12
Given that our previous study found the enantioselective
inhibition of carprofen towards UGT isoforms,13 the present
study aimed to investigate the chirality influence of zaltoprofen
towards UDP-glucuronosyltransferases (UGTs) inhibition
potential.
contrasting, properties for pharmacodynamic and pharmacoki-
netic behaviors. For the anticoagulant drug warfarin, (S)-warfarin
exhibits a stronger therapeutic role than (R)-warfarin. Addi-
2
tionally, different binding of (R)-warfarin and (S)-warfarin with
3
human albumin has been reported. Tramadol and its active
O-demethylated metabolite exhibited stereoselective pharma-
cokinetics in rats.4
UDP-glucuronosyltransferases (UGTs), the important
phase II drug-metabolizing enzyme, plays an important role
in the metabolic elimination of many important clinical drugs.
For example, UGT1A9-catalyzed glucuronidation reaction is
5
the major elimination pathway for propofol. UGT2B7 can cat-
alyze the glucuronidation elimination reaction of anti-HIV
6
drugs, including efavirenz and zidovudine. UGTs also play
*
Correspondence to: Xin Liu, First Affiliated Hospital of Liaoning Medical
an important role in the metabolism of some endogenous sub-
University, Jinzhou, Liaoning, People’s Republic of China. E-mail:
cyf2005yjs@163.com
7,8
stances, including bile acids, estrogen, and bilirubin. The
inhibitory capability of various xenobiotics and endogenous
substances towards the activity of UGT isoforms has been
reported. For example, lipid components showed strong
Received for publication 19 December 2014; Accepted 27 January 2015
DOI: 10.1002/chir.22436
Published online 22 April 2015 in Wiley Online Library
(wileyonlinelibrary.com).
©
2015 Wiley Periodicals, Inc.

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JIA ET AL.
MATERIALS AND METHODS
Chemicals
4
-Methylumbelliferone (4-MU), 4-methylumbelliferone-β-D-glucuronide
(4-MUG), Tris–HCl, 7-hydroxycoumarin, and uridine-5’-diphosphoglucuronic
acid (UDPGA) (trisodium salt) were purchased from Sigma-Aldrich (St. Louis,
MO). Recombinant human UGT isoforms (UGT1A1, UGT1A3, UGT1A6,
UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B4, UGT2B7) expressed in
baculovirus-infected insect cells were obtained from BD Gentest (Woburn,
MA). (R)-zaltoprofen and (S)- zaltoprofen were made according to the previ-
ous literature. The purities for both enantiomers were more than 98.0%. All
other reagents were of high-performance liquid chromatography (HPLC)
grade or of the highest grade commercially available.
Fig. 1. Comparison of the inhibition capability of zaltoprofen enantiomers
towards UGT isoforms. In this screening process, 100 μM of (R)-zaltoprofen
and (S)-zaltoprofen were used. Data are given as mean plus SD (n = 3).
Initial Screening of Zaltoprofen Enantiomers’ Inhibition
Towards Recombinant UGTs-Catalyzed 4-MU
Glucuronidation
Inhibition Kinetic Determination for Zaltoprofen
Enantiomers Towards Representative ugt Isoforms
4
-MU, a nonspecific probe substrate for all the UGT isoforms, was
employed to investigate the inhibition of zaltoprofen enantiomers towards
the activity of UGT isoforms. The incubation and analytical methods have
Due to the stronger inhibition of (R)-zaltoprofen towards
UGT1A8 and UGT2B7 than (S)-zaltoprofen, the inhibition
kinetic behavior of (R)-zaltoprofen towards UGT1A8 and
UGT2B7 was determined. Additionally, UGT1A7 was selected
as an example of UGT isoforms not differently inhibited by
zaltoprofen, and the inhibition kinetic behavior of both
zaltoprofen enantiomers towards UGT1A7 was determined.
As shown in Figure 2A,B, (R)-zaltoprofen exhibited competi-
tive inhibition towards UGT1A7, as indicated by the location
of the intersection point in the second quadrant in the Dixon
plot and in the vertical axis in the Lineweaver–Burk plot. For
9
been previously described. In brief, the typical incubation system (total
volume = 200 μL) contained recombinant UGTs, 5 mM UDPGA, 5 mM
MgCl , 50 mM Tris–HCl (pH = 7.4), and 4-MU in the absence or presence
2
of different concentrations of (R)-zaltoprofen or (S)-zaltoprofen. The com-
pounds were dissolved in DMSO and the final concentration of DMSO
was below 0.5% (v/v). The incubation time and protein concentration have
been demonstrated to ensure the linear glucuronidation reaction. The con-
m
centration of 4-MU used was equal to known K or S50 values reported in
9
the previous literatures. After a 5-min preincubation, UDPGA was added
to initiate the glucuronidation reaction, and after the incubation the reaction
was terminated with 100 μL acetonitrile with 7-hydroxycoumarin (100 μM)
as internal standard. Centrifuged at 22,000g for 10 min, the aliquots (10 μL)
of supernatant were transferred to an autoinjector vial for HPLC analysis.
The analysis instrument (Shimadzu, Kyoto, Japan) contained an SCL-10A
system controller, two LC-10AT pumps, an SIL-10A autoinjector, and an
SPD-10AVP UV detector. Chromatographic separation was carried out
using a C18 column (4.6 × 200 mm, 5 μm, Kromasil) at a flow rate of
(
S)-zaltoprofen, the intersection point was located in the hori-
zontal axis in both Dixon (Figure 3A) and Lineweaver–Burk
Figure 3B) plots. The second plots (Figure 2C,C) were used
(
to calculate the inhibition kinetic parameters (K ) to be 25.1
i
and 35.0 μM μM for (R)-zaltoprofen and (S)-zaltoprofen, respec-
tively. As shown in Figure 4, (R)-zaltoprofen noncompetitively
1
mL/min and UV detector at 316 nm. The mobile phase consisted of
acetonitrile (A) and H O containing 0.5% (v/v) formic acid (B). The follow-
ing gradient condition was used: 0–15 min, 95–40% B; 15–20 min, 10% B;
0–30 min, 95% B. The calculation curve was generated by peak area ratio
4-MUG/internal standard) over the concentration range of 4-MUG
.1–100 mM. The curve was linear over this concentration range, with
inhibited the activity of UGT1A8, and the K value was deter-
2
i
mined to be 35.3 μM. For the inhibition of (R)-zaltoprofen
towards UGT2B7, the inhibition kinetic type was competitive,
and the inhibition kinetic parameter (Ki) was calculated to
be 19.2 μM (Figure 5).
2
(
0
2
r >0.99. The limits of detection and quantification were determined at
signal-to-noise ratios of 3 and 10, respectively. The accuracy and precision
of the back-calculated values for each concentration were less than 5%.
DISCUSSION
Drug–drug interactions remain the limiting factor for the
clinical application of drugs, and the inhibition of drug-
metabolizing enzymes is a key factor for drug–drug interac-
tion.14 Drug-metabolizing enzymes contain phase I (e.g.,
cytochrome P450 (CYP), esterase, etc.) and phase II (e.g.,
UDP-glucuronosyltransferases (UGTs), etc.) enzymes. The
influence of drug chirality on the inhibition potential towards
CYP isoforms has been reported. For example, the experi-
ment performed by Dilmaghanian et al. showed the
enantioselectivity of inhibition of cytochrome P450 3A4
Inhibition Kinetic Determination
Multiple concentrations of 4-MU and (R)-zaltoprofen or (S)-zaltoprofen
were used to determine the reaction velocity. A Dixon plot and
Lineweaver–Burk plot were used to fit the data as previously described.
The inhibition kinetic type was evaluated through determining the intersec-
tion point in the Dixon and Lineweaver–Burk plots. The second plot of
slopes from Lineweaver–Burk plot vs. the concentrations of (R)-zaltoprofen
i
or (S)-zaltoprofen was utilized to calculate the K value.
(
CYP3A4) by ketoconazole.15 The stereoselective interaction
RESULTS
between tetrahydropalmatine enantiomers and CYP enzymes
in human liver microsomes has been reported.
Comparison of Inhibition Capability of Zaltoprofen
Enantiomers Towards ugt Isoforms
16
The present study demonstrated the stereoselective inhibi-
tion of zaltoprofen towards the activity of UGT1A8 and
UGT2B7. UGT1A8 is an important intestinal UGT isoform,
and is involved in the metabolism of some clinical drugs.
For example, UGT1A8 has been reported to exhibit catalytic
activity towards raloxifene, and the UGT1A8 genotype plays
The inhibition potential of (R)-zaltoprofen and (S)-zaltoprofen
is given in Figure 1. Among the tested UGT isoforms, both
R)-zaltoprofen and (S)-zaltoprofen exhibited similar inhibition
potential towards UGT1A1, 1A3, 1A6, 1A7, 1A9, 1A10, and 2B4.
R)-zaltoprofen exhibited stronger inhibition capability to-
(
(
17
wards UGT1A8 and UGT2B7 than (S)-zaltoprofen (P < 0.01,
an important role in the overall response to raloxifene. Addi-
tionally, the activity of UGT1A8 has high correlation with the
Figure 1).
Chirality DOI 10.1002/chir

UGTS INHIBITION BY ZALTOPROFEN ENANTIOMERS
361
Fig. 2. Inhibition kinetics of (R)-zaltoprofen towards UGT1A7-catalyzed glucuronidation of 4-MU. (A) Dixon plot of (R)-zaltoprofen’s inhibition towards UGT1A7-
catalyzed glucuronidation of 4-MU. Each data point represents the mean value of duplicate experiments. (B) Lineweaver–Burk plot of (R)-zaltoprofen’s inhibition
towards UGT1A7-catalyzed glucuronidation of 4-MU. Each data point represents the mean value of duplicate experiments. (C) The second plot of (R)-zaltoprofen’s
inhibition towards UGT1A7-catalyzed glucuronidation of 4-MU.
Fig. 3. Inhibition kinetics of (S)-zaltoprofen towards UGT1A7-catalyzed glucuronidation of 4-MU. (A) Dixon plot of (S)-zaltoprofen’s inhibition towards UGT1A7-
catalyzed glucuronidation of 4-MU. Each data point represents the mean value of duplicate experiments. (B) Lineweaver–Burk plot of (S)-zaltoprofen’s inhibition
towards UGT1A7-catalyzed glucuronidation of 4-MU. Each data point represents the mean value of duplicate experiments. (C) The second plot of (S)-zaltoprofen’s
inhibition towards UGT1A7-catalyzed glucuronidation of 4-MU.
occurrence of cancers.18 UGT2B7 is regarded as one of the
most important UGT isoforms involved in drug metabolism,
such as the glucuronidation process of zidovudine. There-
fore, compared with (S)-zaltoprofen, (R)-zaltoprofen exhibited
higher risk when coadministered with the drugs mainly un-
dergoing UGT1A8 and UGT2B7-catalyzed metabolism.
Kinetic studies were investigated for the inhibition of
(R)-zaltoprofen towards UGT1A8 and UGT2B7. It was found
Chirality DOI 10.1002/chir
1
9

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JIA ET AL.
Fig. 4. Inhibition kinetics of (R)-zaltoprofen towards UGT1A8-catalyzed glucuronidation of 4-MU. (A) Dixon plot of (R)-zaltoprofen’s inhibition towards UGT1A8-
catalyzed glucuronidation of 4-MU. Each data point represents the mean value of duplicate experiments. (B) Lineweaver–Burk plot of (R)-zaltoprofen’s inhibition
towards UGT1A8-catalyzed glucuronidation of 4-MU. Each data point represents the mean value of duplicate experiments. (C) The second plot of (R)-zaltoprofen’s
inhibition towards UGT1A8-catalyzed glucuronidation of 4-MU.
Fig. 5. Inhibition kinetics of (R)-zaltoprofen towards UGT2B7-catalyzed glucuronidation of 4-MU. (A) Dixon plot of (R)-zaltoprofen’s inhibition towards UGT2B7-
catalyzed glucuronidation of 4-MU. Each data point represents the mean value of duplicate experiments. (B) Lineweaver–Burk plot of (R)-zaltoprofen’s inhibition
towards UGT2B7-catalyzed glucuronidation of 4-MU. Each data point represents the mean value of duplicate experiments. (C) The second plot of (R)-zaltoprofen’s
inhibition towards UGT2B7-catalyzed glucuronidation of 4-MU.
that (R)-zaltoprofen exhibited noncompetitive inhibition to-
wards UGT1A8 and competitive inhibition towards UGT2B7.
The inhibition kinetic parameters were calculated to be
Chirality DOI 10.1002/chir
35.3 μM and 19.2 μM for UGT1A8 and UGT2B7, respectively.
It should be noted that the inhibition kinetic type of zaltoprofen
enantiomers towards UGT1A7 (competitive inhibition of

UGTS INHIBITION BY ZALTOPROFEN ENANTIOMERS
363
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R)-zaltoprofen towards UGT1A7, and noncompetitive inhibi-
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8
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kinetic parameters ([I]/Ki) can reflect the in vivo inhibition
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6
.1 for the inhibition of (R)-zaltoprofen towards UGT1A7,
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(
UGT1A8, and (R)-zaltoprofen towards UGT2B7.
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UGT1A8 and UGT2B7 was demonstrated, and a potential
drug–drug interaction might occur between zaltoprofen and
drugs undergoing multiple UGT isoforms-catalyzed metabo-
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was supported by the National Natural Science Foundation
of China (No. 81102460, 81202586, 81202587, 81202588).
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Chirality DOI 10.1002/chir