Screening of non-steroidal anti-inflammatory drugs for inhibitory effects on the activities of six UDP-glucuronosyltransferases (UGT1A1, 1A3, 1A4, 1A6, 1A9 and 2B7) using LC-MS/MS

Jeongmin Joo; Yang Weon Kim; Zhexue Wu; Jung Hoon Shin; Boram Lee; Jong Cheol Shon; Eun Young Lee; Nguyen Minh Phuc; Kwang Hyeon Liu

doi:10.1002/bdd.1933

Screening of non-steroidal anti-inflammatory drugs for inhibitory effects on the activities of six UDP-glucuronosyltransferases (UGT1A1, 1A3, 1A4, 1A6, 1A9 and 2B7) using LC-MS/MS

Jeongmin Joo, Yang Weon Kim, Zhexue Wu, Jung Hoon Shin, Boram Lee, Jong Cheol Shon, Eun Young Lee, Nguyen Minh Phuc, Kwang Hyeon Liu

Research output: Contribution to journal › Article › peer-review

30 Scopus citations

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) are used widely to relieve pain and to decrease inflammation. Several clinical studies have reported that NSAIDs inhibit uridine 5′-diphospho-glucuronosyltransferase (UGT) enzymes. Therefore, the study evaluated the inhibitory potential of 15 NSAIDs on the activities of six UGT isoforms (i.e. UGT1A1, 1A3, 1A4, 1A6, 1A9 and 2B7) in human liver microsomes (HLMs). Among the 15 NSAIDs tested here, mefenamic acid and diclofenac inhibited all UGTs tested in this study. Piroxicam and niflumic acid inhibited UGT1A9 activity (IC₅₀ = 73.8 μm and 0.38 μm, respectively) and naproxen selectively inhibited UGT2B7 activity (IC₅₀ = 53.1 μm), whereas it did not inhibit the other UGTs tested (IC₅₀ > 200 μm). Diflunisal inhibited the UGT1A1 (IC₅₀ = 33.0 μm) and UGT1A9 (IC₅₀ = 19.4 μm). Acetaminophen, fenoprofen, ibuprofen, ketoprofen, meloxicam, phenylbutazone, salicylic acid and sulindac showed negligible inhibitory effects on the six UGTs (IC₅₀ > 100 μm). These results suggest that some NSAIDs have the potential to inhibit UGTs in vitro.

Original language	English
Pages (from-to)	258-264
Number of pages	7
Journal	Biopharmaceutics and Drug Disposition
Volume	36
Issue number	4
DOIs	https://doi.org/10.1002/bdd.1933
State	Published - May 2015

Keywords

drug interaction
LC-MS/MS
microsomes
NSAIDs
UGT

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Joo, J., Kim, Y. W., Wu, Z., Shin, J. H., Lee, B., Shon, J. C., Lee, E. Y., Phuc, N. M., & Liu, K. H. (2015). Screening of non-steroidal anti-inflammatory drugs for inhibitory effects on the activities of six UDP-glucuronosyltransferases (UGT1A1, 1A3, 1A4, 1A6, 1A9 and 2B7) using LC-MS/MS. Biopharmaceutics and Drug Disposition, 36(4), 258-264. https://doi.org/10.1002/bdd.1933

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title = "Screening of non-steroidal anti-inflammatory drugs for inhibitory effects on the activities of six UDP-glucuronosyltransferases (UGT1A1, 1A3, 1A4, 1A6, 1A9 and 2B7) using LC-MS/MS",

abstract = "Non-steroidal anti-inflammatory drugs (NSAIDs) are used widely to relieve pain and to decrease inflammation. Several clinical studies have reported that NSAIDs inhibit uridine 5′-diphospho-glucuronosyltransferase (UGT) enzymes. Therefore, the study evaluated the inhibitory potential of 15 NSAIDs on the activities of six UGT isoforms (i.e. UGT1A1, 1A3, 1A4, 1A6, 1A9 and 2B7) in human liver microsomes (HLMs). Among the 15 NSAIDs tested here, mefenamic acid and diclofenac inhibited all UGTs tested in this study. Piroxicam and niflumic acid inhibited UGT1A9 activity (IC50 = 73.8 μm and 0.38 μm, respectively) and naproxen selectively inhibited UGT2B7 activity (IC50 = 53.1 μm), whereas it did not inhibit the other UGTs tested (IC50 > 200 μm). Diflunisal inhibited the UGT1A1 (IC50 = 33.0 μm) and UGT1A9 (IC50 = 19.4 μm). Acetaminophen, fenoprofen, ibuprofen, ketoprofen, meloxicam, phenylbutazone, salicylic acid and sulindac showed negligible inhibitory effects on the six UGTs (IC50 > 100 μm). These results suggest that some NSAIDs have the potential to inhibit UGTs in vitro.",

keywords = "drug interaction, LC-MS/MS, microsomes, NSAIDs, UGT",

author = "Jeongmin Joo and Kim, {Yang Weon} and Zhexue Wu and Shin, {Jung Hoon} and Boram Lee and Shon, {Jong Cheol} and Lee, {Eun Young} and Phuc, {Nguyen Minh} and Liu, {Kwang Hyeon}",

note = "Publisher Copyright: Copyright {\textcopyright} 2014 John Wiley & Sons, Ltd.",

year = "2015",

month = may,

doi = "10.1002/bdd.1933",

language = "English",

volume = "36",

pages = "258--264",

journal = "Biopharmaceutics and Drug Disposition",

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Screening of non-steroidal anti-inflammatory drugs for inhibitory effects on the activities of six UDP-glucuronosyltransferases (UGT1A1, 1A3, 1A4, 1A6, 1A9 and 2B7) using LC-MS/MS. / Joo, Jeongmin; Kim, Yang Weon; Wu, Zhexue et al.
In: Biopharmaceutics and Drug Disposition, Vol. 36, No. 4, 05.2015, p. 258-264.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

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AU - Joo, Jeongmin

AU - Kim, Yang Weon

AU - Wu, Zhexue

AU - Shin, Jung Hoon

AU - Lee, Boram

AU - Shon, Jong Cheol

AU - Lee, Eun Young

AU - Phuc, Nguyen Minh

AU - Liu, Kwang Hyeon

PY - 2015/5

Y1 - 2015/5

N2 - Non-steroidal anti-inflammatory drugs (NSAIDs) are used widely to relieve pain and to decrease inflammation. Several clinical studies have reported that NSAIDs inhibit uridine 5′-diphospho-glucuronosyltransferase (UGT) enzymes. Therefore, the study evaluated the inhibitory potential of 15 NSAIDs on the activities of six UGT isoforms (i.e. UGT1A1, 1A3, 1A4, 1A6, 1A9 and 2B7) in human liver microsomes (HLMs). Among the 15 NSAIDs tested here, mefenamic acid and diclofenac inhibited all UGTs tested in this study. Piroxicam and niflumic acid inhibited UGT1A9 activity (IC50 = 73.8 μm and 0.38 μm, respectively) and naproxen selectively inhibited UGT2B7 activity (IC50 = 53.1 μm), whereas it did not inhibit the other UGTs tested (IC50 > 200 μm). Diflunisal inhibited the UGT1A1 (IC50 = 33.0 μm) and UGT1A9 (IC50 = 19.4 μm). Acetaminophen, fenoprofen, ibuprofen, ketoprofen, meloxicam, phenylbutazone, salicylic acid and sulindac showed negligible inhibitory effects on the six UGTs (IC50 > 100 μm). These results suggest that some NSAIDs have the potential to inhibit UGTs in vitro.

AB - Non-steroidal anti-inflammatory drugs (NSAIDs) are used widely to relieve pain and to decrease inflammation. Several clinical studies have reported that NSAIDs inhibit uridine 5′-diphospho-glucuronosyltransferase (UGT) enzymes. Therefore, the study evaluated the inhibitory potential of 15 NSAIDs on the activities of six UGT isoforms (i.e. UGT1A1, 1A3, 1A4, 1A6, 1A9 and 2B7) in human liver microsomes (HLMs). Among the 15 NSAIDs tested here, mefenamic acid and diclofenac inhibited all UGTs tested in this study. Piroxicam and niflumic acid inhibited UGT1A9 activity (IC50 = 73.8 μm and 0.38 μm, respectively) and naproxen selectively inhibited UGT2B7 activity (IC50 = 53.1 μm), whereas it did not inhibit the other UGTs tested (IC50 > 200 μm). Diflunisal inhibited the UGT1A1 (IC50 = 33.0 μm) and UGT1A9 (IC50 = 19.4 μm). Acetaminophen, fenoprofen, ibuprofen, ketoprofen, meloxicam, phenylbutazone, salicylic acid and sulindac showed negligible inhibitory effects on the six UGTs (IC50 > 100 μm). These results suggest that some NSAIDs have the potential to inhibit UGTs in vitro.

KW - drug interaction

KW - LC-MS/MS

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KW - UGT

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JO - Biopharmaceutics and Drug Disposition

JF - Biopharmaceutics and Drug Disposition

IS - 4

ER -

Screening of non-steroidal anti-inflammatory drugs for inhibitory effects on the activities of six UDP-glucuronosyltransferases (UGT1A1, 1A3, 1A4, 1A6, 1A9 and 2B7) using LC-MS/MS

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Keywords

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