Metoprolol oxidation polymorphism in Brazilian elderly cardiac patients

Neves, Daniel Valente; Lanchote, Vera Lúcia; Souza, Luiz de; Hayashida, Miyeko; Nogueira, Maria Sueli; Moraes, Natália Valadares de; Cesarino, Evandro José

doi:10.1111/jphp.12109

Cited by 7 publications

(9 citation statements)

References 36 publications

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“…Aliquots of 100 μL of plasma supplemented with tramadol as an internal standard (50 μg/ml), 25 μL of 1 M sodium hydroxide aqueous solution, 10 mg of sodium chloride and 2 mL of dichloromethane-diisopropyl ether (1:1, v/v). The compounds were separated on an RP Select B column (LiChrospher®60 Merck, Darmstadt, Germany) using buffer phosphate (0.05 M and pH 3.5) and acetonitrile (90:10, v/v) as the mobile phase and analyzed using a fluorescence detector (229 and 298 nm) [23, 24]. Calibration curves were constructed from 20 to 1000 ng metoprolol/mL and from 10 to 500 ng α-hydroxymetoprolol/mL.…”

Section: Methodsmentioning

confidence: 99%

Hormonal status affects plasma exposure of tamoxifen and its main metabolites in tamoxifen-treated breast cancer patients

Ximenez

Andrade

Marques

et al. 2019

BMC Pharmacol Toxicol

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BackgroundTamoxifen is considered a prodrug of its active metabolite endoxifen, which is dependent on the CYP2D6 and CYP3A enzymes. Tamoxifen pharmacokinetic variability influences endoxifen exposure and, consequently, its clinical outcome. This study investigated the impact of hormonal status on the pharmacokinetics of tamoxifen and its metabolites in TAM-treated breast cancer patients.MethodsTAM-treated breast cancer patients (n = 40) previously believed to have CYP3A activity within the normal range based on oral midazolam and phenotyped as CYP2D6 normal metabolizers using oral metoprolol were divided into two groups according to premenopausal (n = 20; aged 35–50 years) or postmenopausal (n = 20; aged 60–79 years) status. All patients were treated with 20 mg/day tamoxifen for at least three months. Serial plasma samples were collected within the 24 h dose interval for analysis of unchanged tamoxifen, endoxifen, 4-hydroxytamoxifen and N-desmethyltamoxifen quantified by LC-MS/MS. CYP activities were assessed using midazolam apparent clearance (CYP3A) and the metoprolol/alfa-hydroxymetoprolol plasma metabolic ratio (CYP2D6). CYP3A4, CYP3A5 and CYP2D6 SNPs and copy number variation were investigated using TaqMan assays.ResultsPostmenopausal status increased steady-state plasma concentrations (Css) of tamoxifen (116.95 vs 201.23 ng/mL), endoxifen (8.01 vs 18.87 ng/mL), N-desmethyltamoxifen (485.16 vs 843.88 ng/mL) and 4-hydroxytamoxifen (2.67 vs 4.11 ng/mL). The final regression models included hormonal status as the only predictor for Css of tamoxifen [β-coef ± SE, p-value (75.03 ± 17.71, p = 0.0001)] and 4-hydroxytamoxifen (1.7822 ± 0.4385, p = 0.0002), while endoxifen Css included hormonal status (8.578 ± 3.402, p = 0.02) and race (11.945 ± 2.836, p = 0.007). For N-desmethyltamoxifen Css, the final model was correlated with hormonal status (286.259 ± 76.766, p = 0.0007) and weight (− 8.585 ± 3.060, p = 0.008).ConclusionThe premenopausal status was associated with decreased endoxifen plasma concentrations by 135% compared to postmenopausal status. Thus, the endoxifen plasma concentrations should be monitored mainly in the premenopausal period to maintain plasma levels above the efficacy threshold value.Trial registrationRBR-7tqc7k.

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Section: Methodsmentioning

confidence: 99%

Hormonal status affects plasma exposure of tamoxifen and its main metabolites in tamoxifen-treated breast cancer patients

Ximenez

Andrade

Marques

et al. 2019

BMC Pharmacol Toxicol

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“…The intra-and interday accuracy (relative standard error) and precision (coefficient of variation) ranged from −4.0% to 12.0% and 1.9% to 10.4%, respectively. 22 Pharmacokinetic and Statistical Analysis Noncompartmental analysis was performed using Phoenix 64 WinNonlin software version 8.3.4.295 (Certara, Princeton, NJ, USA). The elimination half-life was derived from the terminal slope of the plasma concentration-time profile.…”

Section: Drug Analysismentioning

confidence: 99%

“…Subjects were stratified as PMs when MR was >12.6. 22,23 Statistical analyses were performed using RStudio Team version 2022.07.1 (R Stats and ggplot2 packages; RStudio, PBC, Boston, MA, USA). The distribution of PK parameters was evaluated by visual inspection of histograms of probability density and quantilequantile graphs, and by the Shapiro-Wilk test.…”

Section: Drug Analysismentioning

confidence: 99%

Effect of Roux‐En‐Y Gastric Bypass in the Pharmacokinetics of (R)‐Carvedilol and (S)‐Carvedilol

Yamamoto

Cristofoletti

Vozmediano

et al. 2023

The Journal of Clinical Pharma

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Roux‐en‐Y gastric bypass is one of the most common surgical treatments for obesity due to the effective long‐term weight loss and remission of associated comorbidities. Carvedilol, a third‐generation β‐blocker, is prescribed to treat cardiovascular diseases. This drug is a weak base with low and pH‐dependent solubility and dissolution and high permeability. As the changes in the gastrointestinal tract anatomy and physiology after roux‐en‐Y gastric bypass can potentially affect drug pharmacokinetics, this study aimed to assess the effect of roux‐en‐Y gastric bypass on the pharmacokinetics of carvedilol enantiomers. Nonobese (n = 15, body mass index < 25 kg/m2), obese (n = 19, body mass index ≥ 30), and post‐roux‐en‐Y gastric bypass subjects submitted to surgery for at least 6 months (n = 19) were investigated. All subjects were administered a single oral dose of 25‐mg racemic carvedilol, and blood was sampled for up to 24 hours. Plasma concentrations of (R)‐ and (S)‐carvedilol were determined by liquid chromatography–tandem mass spectrometry. The maximum plasma concentration (Cmax) and the area under the plasma concentration‐time curve (AUC) of (R)‐carvedilol were 2‐ to 3‐fold higher than (S)‐carvedilol in all groups. Obese subjects have shown reduced Cmax of (R)‐ and (S)‐carvedilol without changing the AUC. Post‐roux‐en‐Y gastric bypass subjects presented a 3.5‐fold reduction in the Cmax of the active (S)‐carvedilol and a 1.9 reduction in the AUC from time 0 to infinity compared to nonobese subjects. The time to reach Cmax of (S)‐carvedilol increased 2.5‐fold in post‐roux‐en‐Y gastric bypass subjects compared to obese or nonobese. Although the β‐blockade response was not assessed, the reduced exposure to carvedilol in subjects post‐roux‐en‐Y gastric bypass may be clinically relevant and require dose adjustment.

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“…Samples. The analytical method of analysis of metoprolol and α-hydroxymetoprolol in plasma samples was developed by high-performance liquid chromatography and fluorescence detector operating at 229 and 298 nm, according to the method previously validated by our research group, 33,34 Analysis of Omeprazole, Hydroxyomeprazole, and Omeprazole Sulfone in Plasma Samples. The analytical method of analysis of omeprazole, hydroxyomeprazole, and omeprazole sulfone in plasma samples was conducted by high-performance liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS), as previously described by our research group.…”

Section: Analysis Of Metoprolol and α-Hydroxymetoprolol In Plasmamentioning

confidence: 99%

“…Samples. The analytical method of analysis of metoprolol and α-hydroxymetoprolol in plasma samples was developed by high-performance liquid chromatography and fluorescence detector operating at 229 and 298 nm, according to the method previously validated by our research group, 33,34 with modifications. Briefly, aliquots of μL of plasma spiked with 25 μL of internal standard solution (tramadol 50 μg/mL) were alkalinized with 250 μL of 1 M sodium hydroxide and extracted with 4 mL of dichloromethane:diisopropyl ether (1:1, v/v) for 30 minutes on a horizontal shaker.…”

Section: Analysis Of Metoprolol and α-Hydroxymetoprolol In Plasmamentioning

confidence: 99%

Nifedipine Does Not Alter the Pharmacokinetics of Venlafaxine Enantiomers in Healthy Subjects Phenotyped for CYP2D6, CYP2C19, and CYP3A

Tozatto

Benzi

Rocha

et al. 2020

The Journal of Clinical Pharma

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Venlafaxine (VEN) is a P‐glycoprotein (P‐gp) substrate, and nifedipine has been described by in vitro and experimental studies as a P‐gp inhibitor. The present study aimed to investigate whether nifedipine alters the kinetic disposition of VEN enantiomers and their metabolites in healthy subjects. A crossover study was conducted in 10 healthy subjects phenotyped as extensive metabolizers for cytochrome P450 (CYP) 2D6, CYP2C19, and CYP3A. In phase 1, the subjects received a single oral dose of 150 mg racemic VEN, and in phase 2, a single oral dose of 40 mg nifedipine was administered with the VEN treatment. Plasma concentrations of VEN enantiomers and their metabolites O‐desmethylvenlafaxine and N, O‐ didesmethylvenlafaxine (ODV and DDV, respectively) were evaluated by liquid chromatography with tandem mass spectrometry up to 72 hours after drug administration. Phase 2 was compared with phase 1 using the 90% confidence interval (CI) of the ratio of geometric means for Cmax and area under the curve (AUC). AUC enantiomeric ratios S‐(+)/R‐(−) were evaluated within each and between phases using the Wilcoxon test (P ≤ .05). The kinetic disposition of VEN was enantioselective (phase 1) with VEN S‐(+)/R‐(−) AUC ratio median of 2.83 (AUC0‐∞, 526 vs 195 ng·h/mL). However, AUC median did not differ between enantiomers for the metabolites ODV (1971 vs 2226 ng·h/mL) and DDV (199 vs 151 ng·h/mL). The 90%CI of the ratio of geometric means showed that the phases are bioequivalent. A single oral dose of 40 mg nifedipine did not alter VEN enantiomer pharmacokinetics in healthy subjects.

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Metoprolol oxidation polymorphism in Brazilian elderly cardiac patients

Abstract: Most of the studied individuals were women, and the proportion of elderly with heart disease classified as PM was smaller than what is usually found among Caucasian populations.

Cited by 7 publications

References 36 publications

Hormonal status affects plasma exposure of tamoxifen and its main metabolites in tamoxifen-treated breast cancer patients

Hormonal status affects plasma exposure of tamoxifen and its main metabolites in tamoxifen-treated breast cancer patients

Effect of Roux‐En‐Y Gastric Bypass in the Pharmacokinetics of (R)‐Carvedilol and (S)‐Carvedilol

Nifedipine Does Not Alter the Pharmacokinetics of Venlafaxine Enantiomers in Healthy Subjects Phenotyped for CYP2D6, CYP2C19, and CYP3A

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