Comparative research on the metabolism of metoprolol by four CYP2D6 allelic variants in vitro with LC-MS/MS

Yang, Qing‐Qing; Sun, Jing; Li, Chuan; Zhang, Haizhi; Xu, Weifeng; Liu, Changxiao; Zheng, Xiaojiao

doi:10.1016/j.jpba.2019.06.016

Cited by 5 publications

(3 citation statements)

References 26 publications

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“…There is mounting evidence implying an increased risk of adverse hemodynamic outcomes due to drug–drug interactions between CYP2D6 inhibitors and beta blockers [ 11 , 12 , 13 , 14 ]. The corollary drug–gene interaction (e.g., using metoprolol in CYP2D6 poor metabolizers) has gained interest in the past decade, and an association between the CYP2D6 metabolizer phenotype and metoprolol serum concentrations seems likely [ 4 , 15 , 16 , 17 , 18 , 19 ]. Several studies have also noted a relationship between CYP2D6 phenotype and clinical outcomes and, in general, a decreasing function of CYP2D6 is associated with lower blood pressure (BP) [ 20 , 21 ] and a decreased heart rate (HR) [ 20 , 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

Metoprolol and CYP2D6: A Retrospective Cohort Study Evaluating Genotype-Based Outcomes

Collett

Massmann

Petry

et al. 2023

JPM

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Metoprolol is a medication commonly utilized in select patients to achieve a reduction in heart rate, systolic blood pressure, or other indications. A majority of metoprolol metabolism occurs via CYP2D6. Decreased expression of the CYP2D6 enzyme increases the concentration of metoprolol. Current pharmacogenomics guidelines by the Dutch Pharmacogenomics Working Group recommend slower titrations and dose decreases to minimize adverse effects from poor metabolizers or normal metabolizers taking concomitant medications that are strong inhibitors of CYP2D6 (phenoconverters). This study aimed to evaluate adverse effects such as bradycardia, hypotension, and syncope in patients who are expected to have absent CYP2D6 enzyme activity due to drug–drug or drug–gene interactions. The secondary aims of this study were to evaluate heart rate measurements for the included participants. Retrospective data were collected for individuals with CYP2D6 genotyping results obtained for clinical purposes. Three categories (CYP2D6 normal metabolizers, poor metabolizers, and phenoconverters) were assigned. A total of 325 participants were included. There was no statistically significant difference found in the primary composite outcome between the three metabolizer groups (p = 0.054). However, a statistically significant difference was identified in the incidences of bradycardia between the poor metabolizers and the normal metabolizers or phenoconverters (p < 0.0001). The average heart rates were 2.8 beats per minute (bpm) and 2.6 bpm lower for the poor metabolizer and phenoconverter groups, respectively, compared to the normal metabolizers (p < 0.0001 for both comparisons). This study further supports the role of genetic testing in precision medicine to help individualize patient care as CYP2D6 poor metabolizers taking metoprolol were found to have an increase in bradycardia. Additional research is needed to clarify the dose relationship in this drug–gene interaction.

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Section: Introductionmentioning

confidence: 99%

Metoprolol and CYP2D6: A Retrospective Cohort Study Evaluating Genotype-Based Outcomes

Collett

Massmann

Petry

et al. 2023

JPM

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“…The most commonly used method to determine the activity of CYP2D6 is to examine its kinetic characteristics of substrate probes [8]. Among them, metoprolol is one of the classic probe drugs [9]. It is a heart selective β-receptor blocker, and is mainly used for treating hypertension, heart failure and angina pectoris.…”

Section: Introductionmentioning

confidence: 99%

“…O-demethylation, N-dealkylation and α-hydroxylation are the main elimination pathways of metoprolol, and nearly 70% of the reaction is catalyzed by CYP2D6 [11]. Among them, α-hydroxymetoprolol is a single-step reaction product that only metabolized by CYP2D6, so it is used to evaluate the activity of CYP2D6 both in vivo and in vitro [9,12].…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and pharmacodynamics characterization of subjects with novel CYP2D6 genotypes using probe drug metoprolol

Qian

Pan

et al. 2022

Preprint

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Purpose To investigate the pharmacokinetic profile and pharmacodynamics characterization of volunteers who carries newly discovered CYP2D6 genotypes. Methods Totally, 22 volunteers were recruited in the study. The peripheral blood and urine were collected at the indicated time after orally administration of metoprolol. After sample preparation, a validated HPLC method was employed to determine metoprolol and α-hydroxymetoprolol. Meanwhile, the blood pressure and electrocardiogram of the subjects were monitored. Results The results demonstrated that the main pharmacokinetic parameters of analytes in CYP2D6*1/*34 were comparable to CYP2D6*1/*1. The AUC and t1/2 in CYP2D6*10/*87, CYP2D6*10/*95 and CYP2D6*97/*97 carriers increased by 2–3 times comparing to wild-type. The urine metabolic rate of metoprolol in these genotypes carriers were in consistence to the tendencies obtained from plasma samples. Therefore, CYP2D6*1/*34 can be assigned as normal metabolizer, while CYP2D6*10/*87, CYP2D6*10/*95 and CYP2D6*97/*97 were intermediate metabolizers. Although the blood concentration of metoprolol is correlated with genotype of CYP2D6, its blood pressure lowering effect is saturated at the maximum efficacy at 25 mmHg. In addition, the P-Q interval prolongation and heart rate lowing were not positively correlated with metoprolol blood exposure. Conclusion Based on the pharmacokinetics-pharmacodynamics model, this study clarified the characteristics of metoprolol with novel CYP2D6 genotypes, and provided a solid basic data for translational medicine of substrate drug.

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Study on the Effect of Three CYP2C9 Variants on Drug–Drug Interaction Related to Six Drugs In Vitro by LC–MS/MS Method

Sun

Yang

et al. 2022

Chromatographia

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Comparative research on the metabolism of metoprolol by four CYP2D6 allelic variants in vitro with LC-MS/MS

Cited by 5 publications

References 26 publications

Metoprolol and CYP2D6: A Retrospective Cohort Study Evaluating Genotype-Based Outcomes

Metoprolol and CYP2D6: A Retrospective Cohort Study Evaluating Genotype-Based Outcomes

Pharmacokinetics and pharmacodynamics characterization of subjects with novel CYP2D6 genotypes using probe drug metoprolol

Study on the Effect of Three CYP2C9 Variants on Drug–Drug Interaction Related to Six Drugs In Vitro by LC–MS/MS Method

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