Development of a LC‐MS/MS method for simultaneous determination of metoprolol and its metabolites, <i>α</i>‐hydroxymetoprolol and <i>O</i>‐desmethylmetoprolol, in rat plasma: application to the herb–drug interaction study of metoprolol and breviscapine

Rao, Zihe; Yue, Ma; Qin, Hong‐Yan; Wang, Yafeng; Yuhui, Wei; Zhou, Yan; Zhang, Guoqiang; Wang, Xingdong; Wu, Xinan

doi:10.1002/bmc.3445

Cited by 13 publications

(6 citation statements)

References 13 publications

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“…Recently Rao et al (2015) developed an LC-MS/MS method for the determination of MET, HM and ODM in rat plasma after administration of 40 mg/kg of MET to rats for DHI. At 40 mg/kg dose, MET will not show first-pass extraction in rat, which may lead to potential bias in the pharmacokinetic analysis of MET, HM and ODM in DDI and DHI issues.…”

Section: Discussionmentioning

confidence: 99%

An evaluation of the CYP2D6 and CYP3A4 inhibition potential of metoprolol metabolites and their contribution to drug–drug and drug–herb interaction by LC‐ESI/MS/MS

Borkar

Bhandi

Dubey

et al. 2016

Biomedical Chromatography

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The aim of the present study was to evaluate the contribution of metabolites to drug-drug interaction and drug-herb interaction using the inhibition of CYP2D6 and CYP3A4 by metoprolol (MET) and its metabolites. The peak concentrations of unbound plasma concentration of MET, α-hydroxy metoprolol (HM), O-desmethyl metoprolol (ODM) and N-desisopropyl metoprolol (DIM) were 90.37 ± 2.69, 33.32 ± 1.92, 16.93 ± 1.70 and 7.96 ± 0.94 ng/mL, respectively. The metabolites identified, HM and ODM, had a ratio of metabolic area under the concentration-time curve (AUC) to parent AUC of ≥0.25 when either total or unbound concentration of metabolite was considered. In vitro CYP2D6 and CYP3A4 inhibition by MET, HM and ODM study revealed that MET, HM and ODM were not inhibitors of CYP3A4-catalyzed midazolam metabolism and CYP2D6-catalyzed dextromethorphan metabolism. However, DIM only met the criteria of >10% of the total drug related material and <25% of the parent using unbound concentrations. If CYP inhibition testing is solely based on metabolite exposure, DIM metabolite would probably not be considered. However, the present study has demonstrated that DIM contributes significantly to in vitro drug-drug interaction. Copyright © 2016 John Wiley & Sons, Ltd.

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Section: Discussionmentioning

confidence: 99%

An evaluation of the CYP2D6 and CYP3A4 inhibition potential of metoprolol metabolites and their contribution to drug–drug and drug–herb interaction by LC‐ESI/MS/MS

Borkar

Bhandi

Dubey

et al. 2016

Biomedical Chromatography

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“…In addition, the strength of the current developed analytical method enables sensitive quantification of multiple drugs. This adds to existing methods that have been designed to measure specific drug classes and lower number of analytes [21,25,32–34]. The high sensitivity of this method also requires minimal serum volumes (20 µL) and therefore could be used in preclinical or clinical studies that have limited available serum.…”

Section: Discussionmentioning

confidence: 99%

Quantification of serum levels in mice of seven drugs (and six metabolites) commonly taken by older people with polypharmacy

Mach

Wang

Hilmer

2020

Fundamemntal Clinical Pharma

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Polypharmacy (use of ≥ 5 drugs) is common in older people but has minimal preclinical or clinical evidence of safety or efficacy and is associated with adverse outcomes in older people. Drug–drug interactions are poorly understood beyond drug pairs. An efficient and sensitive method to measure multiple serum drugs and metabolites could inform drug dosing in polypharmacy. Development of a sensitive liquid chromatography – tandem mass spectrometry method to simultaneously measure seven drugs and their respective metabolites in serum in a preclinical model of polypharmacy. This method was validated for optimal recovery, matrix effect, limit of quantification (LOQ), inter‐ and intra‐day variability, and carry over. Serum samples from mice (n = 5–6/group) treated with chronic oral doses of three polypharmacy regimens and five monotherapies were screened for drug and metabolite levels (metoprolol, α‐hydroxymetoprolol, O‐desmethylmetoprolol, omeprazole, 5‐hydroxyomeprazole, omeprazole sulphone, acetaminophen, irbesartan, citalopram, oxybutynin, oxycodone, noroxycodone, oxymorphone and tenivastatin). The LOQ for the compounds ranged from 0.05 to 0.1 ng/mL in serum. Recovery, matrix effect, and inter‐ and intra‐day variability peak response were acceptable. No carry over was observed at the concentrations tested. Analytes were detectable in mice treated with these drugs, and differences in drug levels were observed with different polypharmacy and monotherapy regimens. The method is sensitive and robust to measure parent drugs and metabolites simultaneously in the context of polypharmacy. Polypharmacy appeared to affect drug levels in a preclinical model. This model can be used to understand pharmacokinetics of chronic polypharmacy, which could inform prescribing and improve outcomes for older people.

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“…Metoprolol and related metabolites are primarily excreted in the urine. The identification of these compounds in urine by LC/MS has been described extensively [20][21][22]. Urinary metabolite abundance was determined using predicted m/z values and associated peak intensities.…”

Section: Metabolomic Analysesmentioning

confidence: 99%

Metabolomic profiling of metoprolol hypertension treatment reveals altered gut microbiota-derived urinary metabolites

et al. 2020

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Introduction: Metoprolol succinate is a long-acting beta-blocker prescribed for the management of hypertension (HTN) and other cardiovascular diseases. Metabolomics, the study of end-stage metabolites of upstream biologic processes, yield insight into mechanisms of drug effectiveness and safety. Our aim was to determine metabolomic profiles associated with metoprolol effectiveness for the treatment of hypertension. Methods: We performed a prospective pragmatic trial (NCT02293096) that enrolled patients between 30 and 80 years with uncontrolled HTN. Patients were started on metoprolol succinate at a dose based upon systolic blood pressure (SBP). Urine and blood pressure measurements were collected weekly. Individuals with a 10% decline in SBP or heart rate (HR) were considered responsive. Genotype for the CYP2D6 enzyme, the primary metabolic pathway for metoprolol, was evaluated for each subject. Unbiased metabolomic analyses were performed on urine samples using UPLC-QTOF mass spectrometry. Results: Urinary metoprolol metabolite ratios are indicative of patient CYP2D6 genotypes. Patients taking metoprolol had significantly higher urinary levels of many gut microbiota-dependent metabolites including hydroxyhippuric acid, hippuric acid, and methyluric acid. Urinary metoprolol metabolite profiles of normal metabolizer (NM) patients more closely correlate to ultra-rapid metabolizer (UM) patients than NM patients. Metabolites did not predict either 10% SBP or HR decline. Conclusion: In summary, urinary metabolites predict CYP2D6 genotype in hypertensive patients taking metoprolol. Metoprolol succinate therapy affects the microbiome-derived metabolites.

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Development of a LC‐MS/MS method for simultaneous determination of metoprolol and its metabolites, α‐hydroxymetoprolol and O‐desmethylmetoprolol, in rat plasma: application to the herb–drug interaction study of metoprolol and breviscapine

Cited by 13 publications

References 13 publications

An evaluation of the CYP2D6 and CYP3A4 inhibition potential of metoprolol metabolites and their contribution to drug–drug and drug–herb interaction by LC‐ESI/MS/MS

An evaluation of the CYP2D6 and CYP3A4 inhibition potential of metoprolol metabolites and their contribution to drug–drug and drug–herb interaction by LC‐ESI/MS/MS

Quantification of serum levels in mice of seven drugs (and six metabolites) commonly taken by older people with polypharmacy

Metabolomic profiling of metoprolol hypertension treatment reveals altered gut microbiota-derived urinary metabolites

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