Inhibitory effects of non-steroidal anti-inflammatory drugs on human liver microsomal morphine glucuronidation: Implications for drug-drug interaction liability

Uchaipichat, Verawan; Rowland, Andrew; Miners, John O.

doi:10.1016/j.dmpk.2021.100442

Cited by 6 publications

(5 citation statements)

References 44 publications

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“…This expression pattern was also reported in several other intersubject analyzes on both organs ( Tables , ) Interestingly, there is a considerable overlap in jejunal and hepatic expression of UGT1A1 and UGT2B7, which explains extensive first pass glucuronidation of some orally administered substrates (e.g., morphine, ezetimibe, and mycophenolic acid) 5,41 . Whereas inhibition of the respective UGT enzymes (e.g., by diclofenac) is not expected to cause clinically relevant interactions, upregulation of UGTs by prototypic enzyme inducers, such as rifampicin was shown to cause significantly changed pharmacokinetics and efficacy of respective substrates 5,42,43 …”

Section: Discussionsupporting

confidence: 76%

“…5,41 Whereas inhibition of the respective UGT enzymes (e.g., by diclofenac) is not expected to cause clinically relevant interactions, upregulation of UGTs by prototypic enzyme inducers, such as rifampicin was shown to cause significantly changed pharmacokinetics and efficacy of respective substrates. 5,42,43 On the contrary, UGT2B17 was almost exclusively found in the jejunum, where it represents the most abundant UGT enzyme as already found in a previous collaboration study. 44 Several endogenous steroids, including testosterone and estradiol but also drugs such as asciminib, vorinostat, and lorcaserin, have been identified as substrates of UGT2B17.…”

Section: Articlesupporting

confidence: 59%

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Comparative Intra‐Subject Analysis of Gene Expression and Protein Abundance of Major and Minor Drug Metabolizing Enzymes in Healthy Human Jejunum and Liver

Wenzel,

Lapczuk‐Romanska,

Malinowski

et al. 2023

Clin Pharma and Therapeutics

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First pass metabolism by phase I and phase II‐enzymes in the intestine and liver is a major determinant of the oral bioavailability of many drugs. Several studies analyzed expressions of major drug‐metabolizing enzymes (DMEs) such as CYP3A4 and UGT1A1 in the human gut and liver. However, there is still a lack of knowledge regarding other DMEs, i.e. “minor” DMEs, although several clinically relevant drugs are affected by those enzymes. Moreover, there is very limited intra‐subject data on hepatic and intestinal expression levels of minor DMEs. To fill this gap of knowledge, we analyzed gene expression (qRT‐PCR) and protein abundance (targeted proteomics) of 24 clinically relevant DMEs, i.e. carboxylesterases (CES), UDP‐glucuronosyltransferases (UGT) and cytochrome P450 (CYP)‐enzymes. We performed our analysis using jejunum and liver tissue specimens from the same 11 healthy organ donors (8 males, 3 females, aged 19‐60 y). Protein amounts of all investigated DMEs, with the exception of CYP4A11, were detected in human liver samples. CES2, CYP2C18, CYP3A4 and UGT2B17 protein abundance was similar or even higher in the jejunum, and all other DMEs were found in higher amounts in the liver. Significant correlations between gene expression and protein levels were observed only for 2 of 15 jejunal, but 13 of 23 hepatic DMEs. Intestinal and hepatic protein amounts only significantly correlated for CYP3A4 and UGT1A3. Our results demonstrated a notable variability between the individuals, which was even higher in the intestine than in the liver. Our intra‐subject analysis of DMEs in the jejunum and liver from healthy donors may be useful for PBPK‐based modelling and prediction in order to improve efficacy and safety of oral drug therapy.

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Section: Discussionsupporting

confidence: 76%

Section: Articlesupporting

confidence: 59%

Comparative Intra‐Subject Analysis of Gene Expression and Protein Abundance of Major and Minor Drug Metabolizing Enzymes in Healthy Human Jejunum and Liver

Wenzel,

Lapczuk‐Romanska,

Malinowski

et al. 2023

Clin Pharma and Therapeutics

View full text Add to dashboard Cite

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“…These studies are described in Table 1 and show that UGT2B7 inhibition leads to decreases in morphine-3-glucuronide and morphine-6-glucuronide formation. Results from one study suggest that inhibition of UGT2B7-mediated morphine metabolism by mefenamic acid would be predicted to lead to a 40% increase in the morphine AUC ( Uchaipichat et al, 2022 ). These in vitro studies highlight the importance of studying UGT-mediated DDIs as they are typically not investigated as readily as CYP-mediated DDIs.…”

Section: Resultsmentioning

confidence: 99%

Hydrocodone, Oxycodone, and Morphine Metabolism and Drug–Drug Interactions

Coates,

Lazarus

2023

J Pharmacol Exp Ther

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Awareness of drug interactions involving opioids is critical for patient treatment as they are common therapeutics used in numerous care settings, including both chronic and disease-related pain. Not only do opioids have narrow therapeutic indexes and are extensively used, but they have the potential to cause severe toxicity. Opioids are the classical pain treatment for patients who suffer from moderate to severe pain. More importantly, opioids are often prescribed in combination with multiple other drugs, especially in patient populations who typically are prescribed a large drug regimen. This review focuses on the current knowledge of common opioid drug–drug interactions (DDIs), focusing specifically on hydrocodone, oxycodone, and morphine DDIs. The DDIs covered in this review include pharmacokinetic DDI arising from enzyme inhibition or induction, primarily due to inhibition of cytochrome p450 enzymes (CYPs). However, opioids such as morphine are metabolized by uridine-5’-diphosphoglucuronosyltransferases (UGTs), principally UGT2B7, and glucuronidation is another important pathway for opioid-drug interactions. This review also covers several pharmacodynamic DDI studies as well as the basics of CYP and UGT metabolism, including detailed opioid metabolism and the potential involvement of metabolizing enzyme gene variation in DDI. Based upon the current literature, further studies are needed to fully investigate and describe the DDI potential with opioids in pain and related disease settings to improve clinical outcomes for patients. SIGNIFICANCE STATEMENT A review of the literature focusing on drug–drug interactions involving opioids is important because they can be toxic and potentially lethal, occurring through pharmacodynamic interactions as well as pharmacokinetic interactions occurring through inhibition or induction of drug metabolism.

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“…Other oral, IV, or subcutaneous opioid PBPK models exist for morphine [ 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ], alfentanil [ 49 , 50 , 51 , 52 ], remifentanil [ 53 , 54 , 55 ], sufentanil [ 56 ], tramadol [ 56 , 57 , 58 , 59 , 60 , 61 ], fentanyl [ 62 , 63 , 64 , 65 , 66 , 67 ], oxycodone [ 40 , 64 , 68 , 69 ], buprenorphine [ 64 , 70 , 71 , 72 , 73 , 74 , 75 ], codeine [ 76 , 77 ], methadone [ 78 , 79 , 80 , 81 , 82 , 83 , 84 ], and carfentanil to predict drug-drug interactions and drug disposition in the plasma and various ...…”

Section: Illegally Used Drugsmentioning

confidence: 99%

An Overview of Physiologically-Based Pharmacokinetic Models for Forensic Science

Fairman

Choi

Gonnabathula

et al. 2023

Toxics

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A physiologically-based pharmacokinetic (PBPK) model represents the structural components of the body with physiologically relevant compartments connected via blood flow rates described by mathematical equations to determine drug disposition. PBPK models are used in the pharmaceutical sector for drug development, precision medicine, and the chemical industry to predict safe levels of exposure during the registration of chemical substances. However, one area of application where PBPK models have been scarcely used is forensic science. In this review, we give an overview of PBPK models successfully developed for several illicit drugs and environmental chemicals that could be applied for forensic interpretation, highlighting the gaps, uncertainties, and limitations.

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Inhibitory effects of non-steroidal anti-inflammatory drugs on human liver microsomal morphine glucuronidation: Implications for drug-drug interaction liability

Cited by 6 publications

References 44 publications

Comparative Intra‐Subject Analysis of Gene Expression and Protein Abundance of Major and Minor Drug Metabolizing Enzymes in Healthy Human Jejunum and Liver

Comparative Intra‐Subject Analysis of Gene Expression and Protein Abundance of Major and Minor Drug Metabolizing Enzymes in Healthy Human Jejunum and Liver

Hydrocodone, Oxycodone, and Morphine Metabolism and Drug–Drug Interactions

An Overview of Physiologically-Based Pharmacokinetic Models for Forensic Science

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