Pharmacokinetics Of Metoprolol Research Articles

Mechanism-Based Inactivation of CYP2D6 by Phellopterin and Related Drug-Drug Interaction with Metoprolol.

Phellopterin (PLP) is a linear furanocoumarin widely found in citrus fruits and herbal medicines. The study aims to comprehensively investigate the mechanism of inhibition of CYP2D6 enzyme activity by PLP and its alteration of metoprolol pharmacokinetics. PLP was found to irreversibly inhibit CYP2D6 in time-, concentration-, and nicotinamide adenine dinucleotide phosphate-dependent manners. Coincubation with quinidine, which is a competitive inhibitor of CYP2D6, attenuated this time-dependent inhibition. Glutathione (GSH) and catalase/superoxide dismutase failed to reverse the PLP-induced CYP2D6 inactivation. GSH trapping experiments provided strong evidence that PLP metabolic activation produces epoxide or γ-ketoaldehyde intermediates. In addition, pretreatment with PLP resulted in significant increases in Cmax and area under curve of plasma metoprolol in rats.

Effect of Ginkgo tablets on the pharmacokinetics of metoprolol in rats: liquid chromatography-tandem mass spectrometry-based study.

This study aimed to assess the interaction between metoprolol and Ginkgo tablets during their co-administration to provide a reference for clinical prescribing. The co-administration of metoprolol (20 mg/kg) and Ginkgo tablets (2.4 mg/kg) was conducted in adult Sprague Dawley (SD) rats (n = 8). An optimized liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the analysis of plasma metoprolol to evaluate its pharmacokinetics. In vitro, the rat liver microsomes were employed to assess the effect of Ginkgo tablets on the metabolic stability of metoprolol and the activity of Cytochrome P450 2D6 (CYP2D6). The developed LC-MS/MS method was demonstrated of high sensitivity, accuracy, and precision. When co-administered with Ginkgo tablets, it increased the area under the curve (AUC, 59.01 ± 10.11 vs. 39.19 ± 10.21 μg/mL × min), the maximum plasma concentration (Cmax, 461.72 ± 44.64 vs. 276.35 ± 118.09 ng/mL), and the half-life (t1/2, 302.83 ± 91.52 vs. 262.34 ± 111.12 min) of metoprolol in rats and reduced the clearance rate (0.346 ± 0.057 vs. 0.539 ± 0.145 L/min/kg). In vitro, Ginkgo tablets improved the metabolic stability of metoprolol and suppressed the activity of CYP2D6 in a concentration-dependent manner with the IC50 value of 11.17 μM. Co-administration of metoprolol with Ginkgo tablets resulted in increasing its systemic exposure through inhibiting CYP2D6 activity.

Pharmacogenomic markers of metoprolol and α-OH-metoprolol concentrations: a genome-wide association study.

Aim: Few genome-wide association studies (GWASs) have been conducted to identify predictors of drug concentrations. The authors therefore sought to discover the pharmacogenomic markers involved in metoprolol pharmacokinetics. Patients & methods: The authors performed a GWAS of a cross-sectional study of 993 patients from the Montreal Heart Institute Biobank taking metoprolol. Results: A total of 391 and 444 SNPs reached the significance threshold of 5×10-8 for metoprolol and α-OH-metoprolol concentrations, respectively. All were located on chromosome 22 at or near the CYP2D6 gene, encoding CYP450 2D6, metoprolol's main metabolizing enzyme. Conclusion: The results reinforce previous findings of the importance of the CYP2D6 locus for metoprolol concentrations and confirm that large biobanks can be used to identify genetic determinants of drug pharmacokinetics at a GWAS significance level.

Intersex and Interspecies Pharmacokinetics of Metoprolol After Oral and Intravenous Dose Administration in Rats and Mice

Aim: Intersex and interspecies metoprolol pharmacokinetics following intravenous and oral dose administration in rodents. Materials & methods: Oral and intravenous dose studies were conducted in rats and mice. Significant intersex differences were observed in peak plasma levels of metoprolol after oral dose in both the species. The plasma concentration (Cmax) was approximately sevenfold higher (270.356 ng/ml) in female compared with male rats (40.981 ng/ml) following oral dose administration. The Cmax observed for male (878.822 ± 75.5 ng/ml) was approximately twofold higher than in female mouse (404.016 ± 113.5 ng/ml) after oral dose administration. Conclusion: Sex and species related physioanatomical characteristics alters metoprolol pharmacokinetics. Such differences should be addressed in studies related to metoprolol interactions with concurrently administered drug candidates.

Effect of hesperetin on the pharmacokinetics of metoprolol succinate in rats

BackgroundMetoprolol is a substrate of CYP3A4, 2B6, CYP2D6, CYP2C9, and p-glycoprotein (p-gp). Hesperetin was reported as an inhibitor of cytochrome P-450 (CYP) enzymes and p-gp. The objective of this study was to investigate the effect of hesperetin on the pharmacokinetics of metoprolol in rats and in vitro models. In in vivo studies, male Wistar rats were treated with metoprolol (30 mg/kg) once a day for 15 consecutive days alone and in combination with hesperetin (25, 50, and 100 mg/kg). Blood samples were withdrawn from the tail vein on the 1st day in the single-dose pharmacokinetic study and on the 15th day in the repeated-dose pharmacokinetic study. In in vitro studies, metoprolol was incubated in the presence or absence of hesperetin and traditional p-gp inhibitors using rat-everted gut sacs. Reverse phase-high-performance liquid chromatography (RP-HPLC) was used to determine the amounts of metoprolol in the plasma and incubated samples (RP-HPLC).ResultsThe Cmax, AUC, and half-life (t1/2) of metoprolol significantly increased by twofold compared to the metoprolol group in rats pre-treated with hesperetin. The clearance and volume of distribution both decreased significantly. Metoprolol transport was dramatically increased in the presence of hesperetin and quinidine (standard p-gp inhibitor) in in vitro study.ConclusionThe present study results revealed that hesperetin significantly increased the absorption of metoprolol in rats and everted gut sacs in vitro might be due to the inhibition of CYP and p-gp.

Physiologically based pharmacokinetic modelling to predict the pharmacokinetics of metoprolol in different CYP2D6 genotypes.

Metoprolol, a selective β1-adrenoreceptor blocking agentused in the treatment of hypertension, angina, and heart failure, is primarily metabolized by the CYP2D6 enzyme, which catalyzes α-hydroxylation and O-desmethylation. As CYP2D6 is genetically highly polymorphic and the enzymatic activity differs greatly depending on the presence of the mutant allele(s), the pharmacokinetic profile of metoprolol is highly variable depending on the genotype of CYP2D6. The aim of study was to develop the physiologically based pharmacokinetic (PBPK) model of metoprolol related to CYP2D6 genetic polymorphism for personalized therapy with metoprolol. For PBPK modelling, our previous pharmacogenomic data were used. To obtain kinetic parameters (Km, Vmax, and CLint) of each genotype, the recombinant CYP enzyme of each genotype was incubated with metoprolol and metabolic rates were assayed. Based on these data, the PBPK model of metoprolol was developed and validated in different CYP2D6 genotypes using PK-Sim® software. As a result, the input values for various parameters for the PBPK model were presented and the PBPK model successfully described the pharmacokinetics of metoprolol in each genotype group. The simulated values were within the acceptance criterion (99.998% confidence intervals) compared with observed values. The PBPK model developed in this study can be used for personalized pharmacotherapy with metoprolol in individuals of various races, ages, and CYP2D6 genotypes.

Inhibitory effects of fluoxetine and duloxetine on the pharmacokinetics of metoprolol in vivo and in vitro.

Depression is common among people with cardiovascular diseases. Therefore, the combined use of antidepressants and cardiovascular drugs is very common, which increases the possibility of drug interaction. Simultaneously compare the effects of duloxetine and fluoxetine on metoprolol metabolism, and provide evidence-based guidance for medication safety. Sprague-Dawley rats were randomly divided into three groups: group A (10.3mg/kg metoprolol alone), group B (10.3mg/kg metoprolol + 6.2mg/kg fluoxetine), and group C (10.3mg/kg metoprolol + 6.2mg/kg duloxetine). Tail vein blood was collected and subjected to the ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) detection. Moreover, in vitro inhibition of fluoxetine and duloxetine were assessed by incubating liver microsomes and CYP2D6.1 with metoprolol. In in vivo study, the administration of fluoxetine or duloxetine significantly increased the AUC(0-𝑡) and AUC(0-∞) of metoprolol (P < 0.05). Differences between fluoxetine and duloxetine in plasma concentration were also investigated, and their pharmacokinetic parameters such as AUC(0-𝑡) and AUC(0-∞) were significantly distinct (P < 0.05). In vitro, fluoxetine and duloxetine inhibited the metabolism of metoprolol via mixed competitive mechanism of cytochrome P450. IC50 values of fluoxetine and duloxetine were 12.86 and 2.51 μM, respectively. Moreover, the metabolism rate of metoprolol was inhibited to 19.62% and 17.14% in recombinant human CYP2D6.1 by fluoxetine and duloxetine, respectively. Duloxetine showed a more significant inhibitory potential compared to fluoxetine in vitro, but the main pharmacokinetic parameters of fluoxetine and duloxetine revealed differences in inhibiting metoprolol metabolism in vivo.

Effects of Astragaloside IV on the Pharmacokinetics of Metoprolol in Rats and its Mechanism.

Astragaloside IV (AST) and metoprolol are often used together to treat cardiovascular diseases, while the herb-drug interaction (HDI) between them is still unclear. This study investigates the effect of AST on the pharmacokinetics of metoprolol in rats and its mechanism to predict the HDI. First, IC50 value of AST on nine CYP450 enzymes in human liver microsomes (HLMs) was determined by the cocktail method. We explored the effect of AST on the pharmacokinetics of metoprolol (metabolized by CYP2D6) in vivo. Twelve male SD rats were equally divided into two groups, with or without pretreatment of AST (3 mg/kg/day) for 7 days, and they received metoprolol (27 mg/kg) by oral administration. Blood samples were determined using HPLC. Finally, the mechanism of AST was explored. AST exhibited a moderate inhibitory effect on CYP2D6 with IC50 value of 32.28 μM. The pharmacokinetic parameters of metoprolol were significantly altered by AST with the increase of AUC0-∞ (538.81 ± 51.41 to 1088.34 ± 86.46 μg*min/mL, P<0.05) and Cmax (6.21 ± 0.56 to 8.34 ± 0.87 μg/ml, P<0.05). The investigation of the mechanism showed AST to be an irreversible inhibitor of CYP2D6 with KI value of 2.9 μM and Kinact of 0.018 min-1, respectively. AST was found to increase the plasma exposure of metoprolol in rats. AST reduced the metabolism of metoprolol by inhibiting CYP2D6 activity. The HDI might enhance when metoprolol and AST will be applied in combination.

Effect of naringenin on the pharmacokinetics of metoprolol succinate in rats

The aim of the present study was to investigate the effect of naringenin (4,5,7-trihydroxy flavonone) on the pharmacokinetics of metoprolol, a substrate of Cytochrome P-450 3A4 (CYP3A4), CYP2C9, and CYP2D6 in rats. Male Wistar rats were treated orally with metoprolol (30 mg/kg) alone and in combination with naringenin (25, 50, and 100 mg/kg) once daily for 15 consecutive days. The plasma concentrations of metoprolol were determined using Reverse Phase-High Performance Liquid Chromatography (RP-HPLC) on the 1st day in single-dose pharmacokinetic (PK) study (SDS) and on the 15th day in multiple dosing PK studies (MDS). Compared to the metoprolol control group, the C max, AUC, and half-life (T 1/2) of metoprolol increased in rats pre-treated with naringenin, while there was no significant change in T max. There is a significant decrease in clearance and volume of distribution. The present study results revealed that naringenin significantly enhanced the C max, AUC, MRT, t 1/2, and decreased the clearance of metoprolol possibly through the inhibition of CYP enzymes involved in the metabolism of metoprolol.

CYP2D6 polymorphism and its impact on the clinical response to metoprolol: A systematic review and meta-analysis.

CYP2D6 genetic polymorphisms are associated with metoprolol pharmacokinetics. Whether the clinical response to metoprolol is also affected remains uncertain. We conducted a systematic review on the effects of CYP2D6 polymorphism on the clinical response to metoprolol. Searches were conducted using MEDLINE. Meta-analyses were performed on the impact of CYP2D6-inferred phenotypes on heart rate (HR) reduction, diastolic (DBP) and systolic (SBP) blood pressure reduction, average daily doses, all-type adverse events and bradycardia. Our qualitative assessment indicated inconsistent results in individual studies and endpoints, but CYP2D6 poor metabolizers (PM) generally presented a greater reduction in HR. The meta-analysis of 15 studies, including a total of 1146 individuals, found a reduction in HR of 3 beats/min (P = .017), and of SBP and DBP by 3 mmHg (P = .0048) for PM compared to non-PM individuals using similar metoprolol doses. Bradycardia appeared more frequent by 4-fold for PM, although significant heterogeneity was observed regarding bradycardia, which limits the scope of this finding. Patients without any CYP2D6 metabolic capacities appear to have increased reduction in DBP, HR and SBP during metoprolol treatment and may be at a higher risk of bradycardia compared to patients with active CYP2D6 phenotypes. Further prospective data are required to determine whether CYP2D6 is associated with clinical events in patients treated with metoprolol, as well as to demonstrate the clinical utility of an individualized approach of prescribing metoprolol using CYP2D6-inferred phenotypes.

Development of a Physiologically Based Pharmacokinetic Model for Metoprolol in Different CYP2D6 Genotypes

Metoprolol, used in the treatment of hypertension, angina, and heart failure, is primarily metabolized by the CYP2D6 enzyme, which catalyzes alpha‐hydroxylation and O‐demethylation. The genetic polymorphism of CYP2D6 leads to differences in the pharmacokinetics of CYP2D6 substrates. Physiologically based pharmacokinetic (PBPK) modeling is a useful tool for predicting the PK profile of drugs that assess the impact of covariates such as demographics, race, and genetic polymorphism. We tested whether the pharmacokinetics of metoprolol was altered by the different CYP2D6 genotypes in Korean subjects. Then, through in vitro study of metoprolol, the metabolic capacity of metoprolol was measured according to the CYP2D6 genotypes. Finally, we developed the PBPK model of metoprolol related to CYP2D6 genetic polymorphism. Forty‐five volunteers were recruited and grouped as CYP2D6 *wt⁄*wt (*wt=1 or 2, n=15), CYP2D6 *wt⁄*5 (n=4), CYP2D6 *wt/*10 (n=9), CYP2D6 *10⁄*10 (n=10), CYP2D6 *5/*10 (n=5) and CYP2D6 *5/*5 (n=2) according to their genotypes. Metoprolol tartrate 100 mg (Betaloc®) was administered orally once to each subject in these six groups. The CYP2D6*1 and CYP2D6*10 were incubated with 10–2000 μM metoprolol for 20 min at 37 □. Then the metabolites were extracted, and the concentration was analyzed by liquid chromatography‐mass spectrometry. The PBPK modeling of metoprolol was developed and optimized using PK‐sim® software. And, PBPK model validation was conducted by comparing the predicted values with observed values from comparison the pharmacokinetic studies. The AUCinf mean of clinical PK data were 492.96, 673.57, 790.15, 2054.61, 3157.16 and 5152.65 ng·h/ml in CYP2D6 *wt⁄*wt, *wt/*10, *wt⁄*5, *10⁄*10, *5⁄*10 and *5⁄*5, respectively. In vitro study, compared with wild‐type CYP2D6 *1 (100%), the intrinsic clearance (Vmax/Km) values of CYP2D6 *10 (0.33 % for α‐hydroxymetoprolol and 0.41 % for O‐desmethylmetoprolol) were significantly altered. Depending on the physico‐chemical parameters, absorption, distribution, metabolism, excretion (ADME) of each genotype, PBPK model of metoprolol was developed using PK‐sim® software. The AUCinf mean of simulated PK data were 468.01, 646.33, 804.03, 2100.12, 3003.65 and 5677.73 ng·h/ml in CYP2D6 *wt⁄*wt, *wt/*10, *wt⁄*5, *10⁄*10, *5⁄*10 and *5⁄*5, respectively. The developed PBPK model of metoprolol successfully described the pharmacokinetics of each CYP2D6 genotype group and its simulated values were within acceptance criterion (99.998% confidence interval). We developed a PBPK model of metoprolol in relation to genetic polymorphism, which predicts the pharmacokinetics of metoprolol, considering demographic data of subjects, physico‐chemical parameters, ADME properties and CYP2D6 genotypes. These results demonstrate the possibility of metoprolol prescription considering the individual genetic differences through this mechanical approach. Furthermore, the PBPK modeling of metoprolol in CYP2D6 genotypes will be applicable to the treatment of various races, ages, and patients.Support or Funding InformationThis research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT, and Future Planning.The observed and predicted metoprolol pharmacokinetic profiles in CYP2D6*wt/*wt, CYP2D6*wt/*10, CYP2D6*wt/*5, CYP2D6*10/*10, CYP2D6*5/*10 and CYP2D6*5/*5 groups.Figure 1

Effect of eliglustat on the pharmacokinetics of digoxin, metoprolol, and oral contraceptives and absorption of eliglustat when coadministered with acid-reducing agents

Eliglustat is an oral substrate reduction therapy indicated for patients with Gaucher disease type 1. Based on in vitro data, clinical trials were conducted to assess the potential for drug-drug interactions between eliglustat and digoxin (P-glycoprotein substrate), metoprolol (sensitive CYP2D6 substrate), a combined oral contraceptive (CYP3A substrate), and acid-reducing agents. Healthy subjects were enrolled in four Phase 1 clinical studies to evaluate the effect of eliglustat on the pharmacokinetics, safety, and tolerability of digoxin (N = 28), metoprolol (N = 14), and a combined oral contraceptive (N = 30) and the effect of acid-reducing agents on eliglustat pharmacokinetics, safety, and tolerability (N = 24). Coadministration resulted in increased exposure to digoxin (1.49-fold) and metoprolol (2-fold) with eliglustat, negligible effects on oral contraceptive pharmacokinetics with eliglustat, and a negligible effect of acid-reducing agents on eliglustat pharmacokinetics. Across all studies, eliglustat was well-tolerated. One serious adverse event (spontaneous abortion) and one discontinuation due to an adverse event (urinary tract infection) were reported, both during the acid-reducing agents study. When eliglustat is coadministered with medications that are P-glycoprotein or CYP2D6 substrates, lower doses of these concomitant medications may be required. Eliglustat may be coadministered with oral contraceptives and acid-reducing agents without dose modifications for either drug.

Evaluation of potential herbal-drug interactions of a standardized propolis extract (EPP-AF®) using an in vivo cocktail approach

Ethnopharmacological relevancePropolis has been employed extensively in many cultures since ancient times as antiseptic, wound healing, anti-pyretic and others due to its biological and pharmacological properties, such as immunomodulatory, antitumor, anti-inflammatory, antioxidant, antibacterial, antiviral, antifungal, antiparasite activities. But despite its broad and traditional use, there is little knowledge about its potential interaction with prescription drugs. Aim of the studyThe main objective of this work was to study the potential herbal-drug interactions (HDIs) of EPP-AF® using an in vivo assay with a cocktail approach. Materials and methodsSubtherapeutic doses of caffeine, losartan, omeprazole, metoprolol, midazolam and fexofenadine were used. Sixteen healthy adult volunteers were investigated before and after exposure to orally administered 125 mg/8 h (375 mg/day) EPP-AF® for 15 days. Pharmacokinetic parameters were calculated based on plasma concentration versus time (AUC) curves. ResultsAfter exposure to EPP-AF®, it was observed decrease in the AUC0−∞ of fexofenadine, caffeine and losartan of approximately 18% (62.20 × 51.00 h.ng/mL), 8% (1085 × 999 h.ng/mL) and 13% (9.01 × 7.86 h.ng/mL), respectively, with all 90% CIs within the equivalence range of 0.80–1.25. On the other hand, omeprazole and midazolam exhibited an increase in AUC0-∞ of, respectively, approximately 18% (18.90 × 22.30 h.ng/mL) and 14% (1.25 × 1.43 h.ng/mL), with the upper bounds of 90% CIs slightly above 1.25. Changes in pharmacokinetics of metoprolol or its metabolite α-hydroxymetoprolol were not statistically significant and their 90% CIs were within the equivalence range of 0.80–1.25. ConclusionsIn conclusion, our study shows that EPP-AF® does not clinically change CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A activities, once, despite statistical significant, the magnitude of the changes in AUC values after EPP-AF® were all below 20% and therefore may be considered safe regarding potential interactions involving these enzymes. Besides, to the best of our knowledge this is the first study to assess potential HDIs with propolis.

Effects of Orotic Acid-Induced Non-Alcoholic Fatty Liver on the Pharmacokinetics of Metoprolol and its Metabolites in Rats.

Preliminary study results have shown that rats with non-alcoholic fatty liver disease (NAFLD) induced by 1% orotic acid-containing diet have decreased hepatic CYP2D activity. This study aims to evaluate the possible pharmacokinetic changes in NAFLD as a result of reduced metabolic activity of CYP2D. The pharmacokinetics of metoprolol and its metabolites, O-desmethyl metoprolol (DMM) and α-hydroxy metoprolol (HM), was investigated in NAFLD and control rats following intravenous (1 mg/kg) and oral (2 mg/kg) administration of metoprolol. The hepatic CYP2D expression was also investigated. NAFLD rats had lower CYP2D expression (by 36.6%) and slower intrinsic clearance (CLint) of metoprolol and formation of HM (by 40.1% and 37.2%, respectively). There were no significant changes in the pharmacokinetics of metoprolol and its metabolites following intravenous administration. In contrast, oral administration of metoprolol resulted in significantly increased total area under plasma concentration-time curve (AUC) of metoprolol (by 127%) and decreased metabolite formation ratios (AUCDMM/AUCMetoprolol [by 42.8%], AUCHM/AUCMetoprolol [by 35.0%]) in NAFLD rats. Moreover, these changes were well correlated with severity of steatosis as quantified by hepatic triglyceride contents. NALFD can lead to a reduction in the hepatic CLint of a drug if it is a substrate of the CYP2D subfamily. The decreased clearance may result in elevated drug concentrations and increased exposure.

A meta-analysis of the effect of CYP2D6 polymorphism on the pharmacokinetics and pharmacodynamics of metoprolol .

To conduct a meta-analysis on the effect of CYP2D6 polymorphism on the pharmacokinetics and pharmacodynamics of metoprolol. A systematic review and meta-analysis of studies on the effect of CYP2D6 polymorphism on metoprolol pharmacokinetics and pharmacodynamics was performed by using the China national knowledge infrastructure (CNKI), database for Chinese technical periodicals (VIP), Wanfang, and PubMed databases up to the end of January 2015. Review Manager 5.3 (the coherence collaboration, www.gradepro.org) and comprehensive Meta-Analysis Software v2 (CMA) Biostat, Englewood, NJ, USA) were used for meta-analysis. A total of 567 cases from 7 studies were included in the present study. Meta-analysis results showed that the area under the curve (AUC)_0-∞ (RR=-6.75, 95% CI (-9.18, -4.31), p<0.00001); C_max (RR=-2.40, 95% CI (-3.25, -1.54), p<0.00001); T_1/2 (RR=-4.81, 95% CI (-6.86, -2.76), p<0.00001); CL/F (RR=1.60, 95% CI (1.03,2.17), p<0.00001); heart rate (RR=1.48, 95% CI (0.03, 2.92), p=0.05), systolic blood pressure (RR=-0.69, 95% CI (-1.85,0.47), p=0.24); and diastolic blood pressure (RR=-1.95, 95% CI (-3.14, -0.76), p=0.001). Begg's funnel plot test showed that the pharmacokinetic parameters (AUC_0-∞, C_max, T_1/2, and CL/F) and pharmacodynamic parameters (HR, DBP, and SBP) were symmetric. Egger's test showed that the pharmacokinetic parameters were asymmetrical, and its intercept was statistically significant (p < 0.05), which was indicative of publication bias. The pharmacodynamic parameter intercept was not statistically significant (p > 0.05), indicating that no publication bias existed. CYP2D6 polymorphism significantly influenced the pharmacokinetic parameters of metoprolol. It also affected heart rate and diastolic blood pressure, whereas systolic pressure was not affected. .

Metoprolol Dose Equivalence in Adult Men and Women Based on Gender Differences: Pharmacokinetic Modeling and Simulations.

Recent meta-analyses and publications over the past 15 years have provided evidence showing there are considerable gender differences in the pharmacokinetics of metoprolol. Throughout this time, there have not been any research articles proposing a gender stratified dose-adjustment resulting in an equivalent total drug exposure. Metoprolol pharmacokinetic data was obtained from a previous publication. Data was modeled using nonlinear mixed effect modeling using the MONOLIX software package to quantify metoprolol concentration–time data. Gender-stratified dosing simulations were conducted to identify equivalent total drug exposure based on a 100 mg dose in adults. Based on the pharmacokinetic modeling and simulations, a 50 mg dose in adult women provides an approximately similar metoprolol drug exposure to a 100 mg dose in adult men.

Pharmacogenomics of heart failure: a systematic review.

Heart failure (HF) and multiple HF-related phenotypes are heritable. Genes implicated in the HF pathophysiology would be expected to influence the response to treatment. We conducted a series of systematic literature searches on the pharmacogenetics of HF therapy to assess the current knowledge on this field. Existing data related to HF pharmacogenomics are still limited. The ADRB1 gene is a likely candidate to predict response to β-blockers. Moreover, the cytochrome P450 2D6 coding gene (CYP2D6) clearly affects the pharmacokinetics of metoprolol, although the clinical impact of this association remains to be established. Given the rising prevalence of HF and related costs, a more personalized use of HF drugs could have a remarkable benefit for patients, caregivers and healthcare systems.

Zero-order metoprolol pharmacokinetics after therapeutic doses: severe toxicity and cardiogenic shock

Objective: Acute beta-blocker overdose can cause severe cardiac dysfunction. Chronic toxicity is rare but potentially severe. We report therapeutic dosing of metoprolol resulting in unusual pharmacokinetics and toxicity, given high-dose insulin therapy for treatment.Case details: A 90-year-old female presented with hypotension, tachycardia and severe cardiac dysfunction after commencing a rapidly increasing metoprolol dose of 250 mg split daily. She was admitted to intensive care and given high-dose insulin therapy (10 U/kg/h), noradrenaline, adrenaline and dobutamine for severe cardiac dysfunction (cardiac index, 0.76 L/min/m2). She developed acute renal failure, ischaemic hepatitis and disseminated intravascular coagulopathy. Inotropes and high-dose insulin were weaned over four days with complete recovery. Metoprolol was quantified with liquid chromatography-tandem mass spectrometry and concentration-time data were analysed using MONOLIX® vs 4.3 (www.lixoft.com). Admission metoprolol concentration was 2.39 μg/mL (therapeutic reference range: 0.035–0.5 μg/mL). Data best fitted a one compartmental model with Michaelis–Menten kinetics and zero order elimination at high concentrations. Final parameter estimates were V, 63.4 L, maximum rate [Vm], 9.57 mg h−1, Michaelis constant [Km], 1.97 mg L−1. Predicted elimination half-life decreased from 20 h over time until there was first order elimination with a half-life 9 h.Conclusion: The time course of cardiac dysfunction was longer than acute overdose but consistent with prolonged zero order elimination of metoprolol, suggesting the patient was a poor CYP2D6 metaboliser. High-dose insulin euglycaemia appeared to be effective in combination with vasoconstrictors/inotropes.

Gender based Dosing of Metoprolol in the Elderly using Population Pharmacokinetic Modeling and Simulations

This article seeks to clarify if gender-based differences occur in the pharmacokinetics of metoprolol in the elderly patients. There are a series of physiologic changes that occur in the elderly ranging from decreased hepatic blood flow to increased adiposity causing higher plasma concentrations at therapeutic doses as compared to the healthy young population. Population pharmacokinetic modeling were performed using MONOLIX and Monte-Carlo simulations were conducted using MATLAB. The data was based from a previously published dataset where elderly patients, having multiple comorbidities, were administered a 50mg dose of metoprolol. Metoprolol was modeled using a one-compartment model and resulted in the following population pharmacokinetic parameters: volume of distribution, V=38L (CV=155%), clearance rates, CL-Men=105L/hour and CL-Women=59.1L/hour (38%), time lag, Tlag=0.469 hour (CV=17%), and the absorption rate constant, Ka=0.235 hr-1 (CV=23%). Gender stratified doses resulting in an equivalent systemic metoprolol exposure in geriatric patients have been identified. Metoprolol doses resulting a similar AUC in a healthy young male administered 50mg tablet were 15mg for geriatric women and 25mg for geriatric men. Further, Metoprolol doses of 25mg for geriatric women and 50mg for geriatric men resulted in an equivalent AUC to a healthy young males dosed with a 100mg tablet. A 15mg Metoprolol tablet may need to be compounded to account for the gender differences in Metoprolol pharmacokinetics.

Development and validation of a liquid chromatography–mass spectrometry method for simultaneous determination of metoprolol and telmisartan in rat plasma and its application to pharmacokinetic study

A simple, rapid and sensitive high-performance liquid chromatography–tandem mass spectrometry method has been developed and validated according to the Food and Drug Administration (FDA) guidelines for simultaneous determination of metoprolol and telmisartan in rat plasma using atorvastatin as an internal standard. The analytes were separated on a Gemini C18 column (50 mm × 4.6 mm, 5 µm) with an isocratic mobile phase of methanol–water containing 0.5 % formic acid (9:1, v/v) at a flow rate of 0.5 mL/min. The estimation was carried out by triple quadrupole mass spectrometry using electrospray ionization technique, operating in multiple reaction monitoring and positive ion modes. Simple liquid–liquid extraction was used for sample preparation. Linearity was achieved over the concentration range of 1–500 ng/mL for both the analytes in rat plasma. Results of validation parameters of the method were with the acceptance criteria of the FDA guidelines. The method was found suitable to quantitatively assess the pharmacokinetics of metoprolol and telmisartan in rat following administration of a single oral dose 2.5 and 2 mg/kg body weight, respectively in Wistar albino rat.