Impact of cytochrome P450 variation on meperidine<i>N</i>-demethylation to the neurotoxic metabolite normeperidine

Murray, Jessica L.; Mercer, Susan L.; Jackson, Klarissa D.

doi:10.1080/00498254.2019.1599465

Cited by 7 publications

(6 citation statements)

References 35 publications

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“…It should be noted that CYP2C19 enzyme activity was also not associated with CYP2C19 genotype. This finding is consistent with our previous report demonstrating high variability in CYP2C19 activity even among donors of the same CYP2C19 genotype (Murray et al, 2020). These data suggest that factors besides CYP2C19 polymorphism influence CYP2C19 activity and CBD 7-hydroxylation.…”

Section: Dmd-ar-2020-000350r2supporting

confidence: 93%

“…Donors included 17 adult males (M) and two adult females (F). Donor CYP2C19 activity, measured as the rate of S-mephenytoin 4´-hydroxylation, was determined previously (Murray et al, 2020). Donor CYP3A4 activity, measured as the rate of testosterone 6βhydroxylation, was provided by suppliers for the individual HLM (Table S1).…”

Section: Cbd Metabolite Formation By Individual Cyp2c19-genotyped Hlmmentioning

confidence: 99%

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Cytochrome P450–Catalyzed Metabolism of Cannabidiol to the Active Metabolite 7-Hydroxy-Cannabidiol

Beers

Jackson

2021

Drug Metab Dispos

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Cannabidiol (CBD) is a naturally occurring, non-psycho-toxic phytocannabinoid that has gained increasing attention as a popular consumer product and for its use in FDA-approved Epidiolex® (CBD oral solution) for the treatment of Lennox-Gastaut syndrome and Dravet syndrome. CBD was previously reported to be metabolized primarily by cytochrome P450 (CYP) 2C19 and CYP3A4, with minor contributions from UDP-glucuronosyltransferases. 7-Hydroxy-CBD (7-OH-CBD) is the primary active metabolite with equipotent activity compared to CBD. Given the polymorphic nature of CYP2C19, we hypothesized that variable CYP2C19 expression may lead to interindividual differences in CBD metabolism to 7-OH-CBD. The objectives of this study were to further characterize the roles of CYP enzymes in CBD metabolism, specifically to the active metabolite 7-OH-CBD, and to investigate the impact of CYP2C19 polymorphism on CBD metabolism in genotyped human liver microsomes. The results from reaction phenotyping experiments with recombinant CYP enzymes and CYP-selective chemical inhibitors indicated that both CYP2C19 and CYP2C9 are capable of CBD metabolism to 7-OH-CBD. CYP3A played a major role in CBD metabolic clearance via oxidation at sites other than the 7-position. In genotyped human liver microsomes, 7-OH-CBD formation was positively correlated with CYP2C19 activity but was not associated with CYP2C19 genotype. In a subset of single-donor human liver microsomes with moderate to low CYP2C19 activity, CYP2C9 inhibition significantly reduced 7-OH-CBD formation, suggesting that CYP2C9 may play a greater role in CBD 7hydroxylation than previously thought. Collectively, these data indicate that both CYP2C19 and CYP2C9 are important contributors in CBD metabolism to the active metabolite 7-OH-CBD.

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Section: Dmd-ar-2020-000350r2supporting

confidence: 93%

Section: Cbd Metabolite Formation By Individual Cyp2c19-genotyped Hlmmentioning

confidence: 99%

Cytochrome P450–Catalyzed Metabolism of Cannabidiol to the Active Metabolite 7-Hydroxy-Cannabidiol

Beers

Jackson

2021

Drug Metab Dispos

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“…It is known as meperidine in the United States because it is widely used to relieve severe and chronic pain, and reduce shivering induced by post anesthesia (1,2). The mechanism of action of pethidine is by working as a μ-agonist opioid (3)(4)(5). Like other opioid drugs, pethidine has several side effects such as pruritus, tolerance, vomiting, respiratory depression, or dependence (6).…”

Section: Introductionmentioning

confidence: 99%

“…Since tramadol is not categorized as a pure opioid, it acts on the central nervous system and has little binding capacity at the μ-opioid receptor. Besides, it affects the serotonergic and noradrenergic systems (3)(4)(5). Many European nations have recently approved tramadol as an analgesic (9).…”

Section: Introductionmentioning

confidence: 99%

Simultaneous determination of pethidine pharmacokinetics in rats: The impact of tramadol coadministration

Mousa¹,

Mahmood²,

Mohammed³

2023

IJVS

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The rats model has never thoroughly investigated the influence of tramadol on plasma pethidine concentration besides pethidine pharmacokinetics. Individually, analgesic ED50s for pethidine and tramadol are estimated as 3.55 and 24.21 mg/kg, i.p. Subsequently, their measures decreased to 1.65 and 11.27 mg/kg, i.p., when both were given in combination at 1:1 from ED50s. Tramadol and pethidine have a form of synergistic analgesic interaction, which is therefore classified as a pharmacodynamic interaction. Pethidine (7.1mg/kg, i.p.) reveals the plasma concentration of 369. 00, 493.33, 373.33, 305.33, 306.33 and 247.67 µg/ml that was measured over distinctive times of 0.25,0.5,1,2,4, and 24 hours. At the same time, the concentration of plasma levels of tramadol and pethidine (48.42 and 7.1mg/kg, i.p., correspondingly) declined to 229.

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“…In addition to opioid and anticholinergic properties, meperidine is serotonergic via inhibition of the serotonin re-uptake transporter, resulting in increased intrasynaptic serotonin [ 2 ]. The most important pathway for meperidine metabolism involves n-demethylation by cytochrome P450 2B6, 2C19, and 3A4 enzymes to normeperidine [ 3 ]. Normeperidine is renally excreted with a half-life of 14 to 48 h [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

Pronounced Declines in Meperidine in the US: Is the End Imminent?

et al. 2022

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Background: Once a widely used analgesic in the United States (US), meperidine offered an alternative opioid to other opioids as a pain reliever and was widely assumed to be safer with acute pancreatitis. However, within the last two decades meperidine, has gone from a frequently used drug to being used only when patients exhibit atypical reactions to opioids (e.g., morphine and hydromorphone), to being taken off the World Health Organization List of Essential Medications and receiving strong recommendations for overall avoidance. The aim of this study was to identify changes in meperidine distribution in the US, and regional disparities as reported to the Drug Enforcement Administration’s Automation of Reports and Consolidated Orders System (DEA ARCOS) and Medicaid. Methods: Data related to meperidine distribution was obtained through ARCOS (2001–2021) and Medicaid public use files (2016–2021). Heat maps were used to visualize regional disparities in distribution by state. States outside a 95% confidence interval were statistically significant. Results: Meperidine distribution between 2001 and 2021 decreased by 97.4% (R = −0.97, p < 0.0001). There was a 34-fold state-level difference in meperidine distribution between Arkansas (16.8 mg/10 persons) and Connecticut (0.5 mg/10 persons) in 2020. Meperidine distribution in 2020 was elevated in Arkansas, Mississippi, and Alabama. In 2021, meperidine distribution was highest in Arkansas (16.7 mg/10 persons) and lowest in Connecticut (0.8 mg/10 persons). Total prescriptions of meperidine as reported by Medicaid decreased by 73.8% (R = −0.67, p = 0.045) between 2016 and 2021. Conclusion: We observed a decrease in the overall distribution of meperidine in the past two decades, with a similar recent decline in prescribing it to Medicaid enrollees. The shortage of some parenteral formulations is an important contributor to these declines, however, the most likely explanation for this global decline in use is related to an increased recognition of safety concerns related to important drug interactions and a neurotoxic metabolite. This data may reflect plans to phase out the use of this opioid, especially in the many situations where safer and more preferred opioids are available.

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Impact of cytochrome P450 variation on meperidineN-demethylation to the neurotoxic metabolite normeperidine

Cited by 7 publications

References 35 publications

Cytochrome P450–Catalyzed Metabolism of Cannabidiol to the Active Metabolite 7-Hydroxy-Cannabidiol

Cytochrome P450–Catalyzed Metabolism of Cannabidiol to the Active Metabolite 7-Hydroxy-Cannabidiol

Simultaneous determination of pethidine pharmacokinetics in rats: The impact of tramadol coadministration

Pronounced Declines in Meperidine in the US: Is the End Imminent?

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