Reviewing pharmacogenetics to advance precision medicine for opioids

Magarbeh, Leen; Gorbovskaya, Ilona; Foll, Bernard Le; Jhirad, Reuven; Müller, Daniel J.

doi:10.1016/j.biopha.2021.112060

Cited by 17 publications

(28 citation statements)

References 194 publications

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“…Missense mutations due to single-nucleotide polymorphisms (SNPs) or base deletions or insertions have been associated either to the loss of or reduction in function, or to a functional conservation over certain substrates (as per the PharmVar database; https://www.pharmvar.org, accessed on 4 October 2021). The combinations of allelic variants known as haplotypes have differential arrangements within the human genome with four key phenotypes, namely ultra-rapid, extensive, intermediate and poor metabolisers (UM, EM, IM and PM) [6,7]. Frequencies for CYP2D6 allelic variants are variable across human populations of different geographical origins and even differ within the same population.…”

Section: Introductionmentioning

confidence: 99%

A Computational Understanding of Inter-Individual Variability in CYP2D6 Activity to Investigate the Impact of Missense Mutations on Ochratoxin A Metabolism

Dorne

Cirlini

Louisse

et al. 2022

Toxins

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Cytochrome P-450 (CYP) enzymes have a key role in the metabolism of xenobiotics of food origin, and their highly polymorphic nature concurs with the diverse inter-individual variability in the toxicokinetics (TK) and toxicodynamics (TD) of food chemicals. Ochratoxin A is a well-known mycotoxin which contaminates a large variety of food and is associated with food safety concerns. It is a minor substrate of CYP2D6, although the effects of CYP2D6 polymorphisms on its metabolism may be overlooked. Insights on this aspect would provide a useful mechanistic basis for a more science-based hazard assessment, particularly to integrate inter-individual differences in CYP2D6 metabolism. This work presents a molecular modelling approach for the analysis of mechanistic features with regard to the metabolic capacity of CYP2D6 variants to oxidise a number of substrates. The outcomes highlighted that a low-frequency CYP2D6 variant (CYP2D6*110) is likely to enhance ochratoxin A oxidation with possible consequences on TK and TD. It is therefore recommended to further analyse such TK and TD consequences. Generally speaking, we propose the identification of mechanistic features and parameters that could provide a semi-quantitative means to discriminate ligands based on the likelihood to undergo transformation by CYP2D6 variants. This would support the development of a fit-for-purpose pipeline which can be extended to a tool allowing for the bulk analysis of a large number of compounds. Such a tool would ultimately include inter-phenotypic differences of polymorphic xenobiotic-metabolising enzymes in the hazard assessment and risk characterisation of food chemicals.

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Section: Introductionmentioning

confidence: 99%

A Computational Understanding of Inter-Individual Variability in CYP2D6 Activity to Investigate the Impact of Missense Mutations on Ochratoxin A Metabolism

Dorne

Cirlini

Louisse

et al. 2022

Toxins

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“…As a result, UM patients are liable to the adverse effects, while PM patients experience a poor analgesic effect [14,15]. Two recent systematic reviews have summarized the current knowledge of the impact of pharmacogenetics on opioids [16,17]. Although NSAIDs and antidepressants are important pillars in the current treatment strategies of pain, associations between the pharmacogenetically relevant SNPs and changes in the safety and efficacy of these drug groups are still controversial.…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenetics and Pain Treatment with a Focus on Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Antidepressants: A Systematic Review

et al. 2022

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Background: This systematic review summarizes the impact of pharmacogenetics on the effect and safety of non-steroidal anti-inflammatory drugs (NSAIDs) and antidepressants when used for pain treatment. Methods: A systematic literature search was performed according to the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines regarding the human in vivo efficacy and safety of NSAIDs and antidepressants in pain treatment that take pharmacogenetic parameters into consideration. Studies were collected from PubMed, Scopus, and Web of Science up to the cutoff date 18 October 2021. Results: Twenty-five articles out of the 6547 initially detected publications were identified. Relevant medication–gene interactions were noted for drug safety. Interactions important for pain management were detected for (1) ibuprofen/CYP2C9; (2) celecoxib/CYP2C9; (3) piroxicam/CYP2C8, CYP2C9; (4) diclofenac/CYP2C9, UGT2B7, CYP2C8, ABCC2; (5) meloxicam/CYP2C9; (6) aspirin/CYP2C9, SLCO1B1, and CHST2; (7) amitriptyline/CYP2D6 and CYP2C19; (8) imipramine/CYP2C19; (9) nortriptyline/CYP2C19, CYP2D6, ABCB1; and (10) escitalopram/HTR2C, CYP2C19, and CYP1A2. Conclusions: Overall, a lack of well powered human in vivo studies assessing the pharmacogenetics in pain patients treated with NSAIDs or antidepressants is noted. Studies indicate a higher risk for partly severe side effects for the CYP2C9 poor metabolizers and NSAIDs. Further in vivo studies are needed to consolidate the relevant polymorphisms in NSAID safety as well as in the efficacy of NSAIDs and antidepressants in pain management.

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“…There is strong evidence that CYP2D6 plays an important role in the metabolism of several commonly prescribed opioid pain medications, including oxycodone [11][12][13][14], codeine [15], tramadol [11,14,16], and hydrocodone [14,17,18]. The product of the CYP2D6 gene, CYP2D6, is the primary enzyme that metabolizes each of these medications into Pharmaceutics 2022, 14, 1863 2 of 12 the active metabolites that provide the majority of analgesia [14].…”

Section: Introductionmentioning

confidence: 99%

“…The product of the CYP2D6 gene, CYP2D6, is the primary enzyme that metabolizes each of these medications into Pharmaceutics 2022, 14, 1863 2 of 12 the active metabolites that provide the majority of analgesia [14]. Specifically, CYP2D6 metabolizes oxycodone into oxymorphone [11], codeine into morphine [15], tramadol into O-desmethyltramadol [11], and hydrocodone into hydromorphone [18].…”

Section: Introductionmentioning

confidence: 99%

Patient Perceptions and Potential Utility of Pharmacogenetic Testing in Chronic Pain Management and Opioid Use Disorder in the Camden Opioid Research Initiative

et al. 2022

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Pharmacogenetics (PGx) has the potential to improve opioid medication management. Here, we present patient perception data, pharmacogenetic data and medication management trends in patients with chronic pain (arm 1) and opioid use disorder (arm 2) treated at Cooper University Health Care in Camden City, NJ. Our results demonstrate that the majority of patients in both arms of the study (55% and 65%, respectively) are open to pharmacogenetic testing, and most (66% and 69%, respectively) believe that genetic testing has the potential to improve their medical care. Our results further support the potential for CYP2D6 PGx testing to inform chronic pain medication management for poor metabolizers (PMs) and ultrarapid metabolizers (UMs). Future efforts to implement PGx testing in chronic pain management, however, must address patient concerns about genetic test result access and genetic discrimination.

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Reviewing pharmacogenetics to advance precision medicine for opioids

Cited by 17 publications

References 194 publications

A Computational Understanding of Inter-Individual Variability in CYP2D6 Activity to Investigate the Impact of Missense Mutations on Ochratoxin A Metabolism

A Computational Understanding of Inter-Individual Variability in CYP2D6 Activity to Investigate the Impact of Missense Mutations on Ochratoxin A Metabolism

Pharmacogenetics and Pain Treatment with a Focus on Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Antidepressants: A Systematic Review

Patient Perceptions and Potential Utility of Pharmacogenetic Testing in Chronic Pain Management and Opioid Use Disorder in the Camden Opioid Research Initiative

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