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; Shin, Jung-Hoon; Lee, Boram; Shon, Jong Cheol; Lee, Eun Young; Phuc, Nguyen Minh; Liu, Kwang-Hyeon

doi:10.1002/bdd.1933

Cited by 29 publications

(11 citation statements)

References 30 publications

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“…However, it showed a lower detection signal than testosterone in the proposed LC‐MS/MS method. The cocktail incubation technique has been used in order to screen simultaneously the activities of several enzymes such as multiple cytochrome P450s or uridine diphosphate glucuronosyltransferases (UGTs) . It is important to optimize substrate concentrations in substrate cocktail incubations to minimize interactions between substrates.…”

Section: Resultsmentioning

confidence: 99%

Simultaneous evaluation of substrate‐dependent CYP3A inhibition using a CYP3A probe substrates cocktail

Lee

Shon

Liu

2016

Biopharm & Drug Disp

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Cytochrome P450 (P450) 3A (CYP3A) is an enzyme responsible for the metabolism of therapeutic drugs such as midazolam, nifedipine, testosterone and triazolam. It is involved in 40% of all cases of P450-mediated metabolism of marketed drugs. Therefore, it is important to evaluate the CYP3A-mediated drug interaction potential of new chemical entities (NCEs). In the past, one P450 isoform-specific probe substrate has been used at a time to evaluate the degree of inhibition of P450 isoforms by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). However, CYP3A enzymes have been shown to have a multi-substrate binding site. Therefore, multiple CYP3A substrates should be used to evaluate precisely the drug interaction potential of NCEs with the enzyme CYP3A. In this study, a method of screening NCEs for their potential to inhibit by CYP3A enzyme activity was developed. It involves the employment of a CYP3A substrate cocktail (including midazolam, testosterone and nifedipine). The concentration of each CYP3A probe substrate in vitro was optimized (0.1 μm for midazolam, 2 μm for testosterone and 2 μm for nifedipine) to minimize mutual drug interactions among probe substrates. The method was validated by comparing inhibition data obtained from the incubation of CYP3A with each individual substrate with data from incubation with a cocktail of all three substrates. The CYP3A inhibition profiles from the substrate cocktail approach were similar to those from the individual substrates approach. This new method could be an effective tool for the robust and accurate screening of the CYP3A inhibition potential of NCEs in drug discovery. Copyright © 2016 John Wiley & Sons, Ltd.

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Section: Resultsmentioning

confidence: 99%

Simultaneous evaluation of substrate‐dependent CYP3A inhibition using a CYP3A probe substrates cocktail

Lee

Shon

Liu

2016

Biopharm & Drug Disp

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“…An in vitro study on human liver microsomes suggested that certain nonsteroidal anti-inflammatory drugs may have an inhibitory potential on UDP-GT isoforms, suggesting that certain mediators of the cyclooxygenase-dependent pathway may be involved in the regulation of DMET activity. However, the underlying mechanism and the clinical relevance in terms of UDP-GT substrate clearance need to be further investigated ( Joo et al, 2015 ).…”

Section: Regulation Of Dmets By Inflammationmentioning

confidence: 99%

Inflammation is a major regulator of drug metabolizing enzymes and transporters: Consequences for the personalization of drug treatment

Stanke‐Labesque

Gautier-Veyret

Chhun

et al. 2020

Pharmacology & Therapeutics

131

147

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Inflammation is an evolutionary process that allows survival against acute infection or injury. Inflammation is also a pathophysiological condition shared by numerous chronic diseases. In addition, inflammation modulates important drug-metabolizing enzymes and transporters (DMETs), thus contributing to intra- and interindividual variability of drug exposure. A better knowledge of the impact of inflammation on drug metabolism and its related clinical consequences would help to personalize drug treatment. Here, we summarize the kinetics of inflammatory mediators and the underlying transcriptional and post-transcriptional mechanisms by which they contribute to the inhibition of important DMETs. We also present an updated overview of the effect of inflammation on the pharmacokinetic parameters of most of the drugs that are DMET substrates, for which therapeutic drug monitoring is recommended. Furthermore, we provide opinions on how to integrate the inflammatory status into pharmacogenetics, therapeutic drug monitoring, and population pharmacokinetic strategies to improve the personalization of drug treatment for each patient.

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“…The use of single doses may be perceived as a limitation. However, neither bazedoxifene nor ibuprofen has been implicated in the induction or inhibition of UGT or CYP2C9; both have multiple‐dose pharmacokinetics that are well predicted by single‐dose observations, and both can be assayed easily after single doses, permitting clear assessment of changes in pharmacokinetics. The results of this study would be expected to predict what would occur after multiple doses and further represent the more common clinical condition, at least for ibuprofen, which is commonly taken as a single dose for treatment of acute pain.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic Drug Interaction Study of Bazedoxifene and Ibuprofen

McKeand

Baird-Bellaire²,

Ermer³

et al. 2018

Clinical Pharm in Drug Dev

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The purpose of this article was to evaluate the potential for a pharmacokinetic interaction between bazedoxifene and ibuprofen. In a randomized crossover study, 12 healthy postmenopausal women (aged 45-65 years) received either a single oral dose of ibuprofen (600-mg tablet), bazedoxifene (20-mg capsule), or both ibuprofen and bazedoxifene during the 3 treatment periods. Serial blood samples were collected for pharmacokinetic analyses. There was no relationship between the UGT1A1 genotype and bazedoxifene clearance. The 90% log-transformed confidence intervals (CIs) for bazedoxifene C , 96% to 144%, and AUC, 85% to 134%, were slightly above the bioequivalence limits of 80% to 125%. The 90% log-transformed CIs for ibuprofen pharmacokinetic parameters were within these limits (C , 92%-122%; AUC, 94%-106%). The increase in bazedoxifene plasma concentrations when combined with ibuprofen versus bazedoxifene alone is unlikely to be clinically significant. The lack of interaction between bazedoxifene and ibuprofen suggests that they may be coadministered without dose adjustment.

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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

Cited by 29 publications

References 30 publications

Simultaneous evaluation of substrate‐dependent CYP3A inhibition using a CYP3A probe substrates cocktail

Simultaneous evaluation of substrate‐dependent CYP3A inhibition using a CYP3A probe substrates cocktail

Inflammation is a major regulator of drug metabolizing enzymes and transporters: Consequences for the personalization of drug treatment

Pharmacokinetic Drug Interaction Study of Bazedoxifene and Ibuprofen

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