Metabolism Of Metoprolol Research Articles

Pharmacogenetic Considerations in Beta-Blocker Therapy

Pharmacogenetic testing offers a promising approach to personalizing beta-blocker therapy which is used for a variety of diseases, such as heart failure, myocardial infarction and migraine prophylaxis. The genetic variability in the metabolism and response to beta-blockers such as metoprolol can significantly influence treatment outcomes. Understanding these genetic differences can help optimize therapy and minimize adverse effects. A brief summary of the current guideline and recommendations: Approximately 0.3-6.5% (depending on their ancestry) of patients are CYP2D6 poor metabolizers. CYP2D6 Poor Metabolizers have significantly decreased metabolism of metoprolol, leading to increased drug concentration and a higher risk of adverse effects. The highest dose of metoprolol that patients can tolerate may be lower in CYP2D6 poor metabolizers compared to those that are non-poor CYP2D6 metabolizers. Current evidence is insufficient to support routine clinical testing or therapeutic adjustments for other genes affecting beta-blocker pharmacodynamics, such as ADRB1, ADRB2, ADRA2C, and GRK5. Future research should consider the combined effects of multiple genetic variants (e.g., polygenic risk scores) rather than focusing solely on single-gene associations.

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

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.

Effects of Water Miscible Organic Co-solvents on Enzyme Kinetic Parameters of Drug Metabolizing Enzymes in Rat Liver Microsomes

We have investigated the effects of methanol, acetonitrile, dimethyl sulphoxide or dioxane on enzyme kinetic parameters (Km and Vmax) of p-nitrophenol hydroxylation, phenacetin deethylation and metoprolol metabolism in rat liver microsomes, at different solvent concentrations. In the case of p-nitrophenol hydroxylation, methanol (0.1 %-0.75 % v/v) and dimethyl sulphoxide (0.01 %-0.075 % v/v) showed 1.3 and 2.5-fold increase respectively, in the Km with a less marked effect on the Vmax. In contrast, dimethyl sulphoxide (0.1 %-0.75% v/v) showed a 1.96-fold decrease in the Vmax. Unlike, methanol and dimethyl sulphoxide, acetonitrile showed activation of the p-nitrophenol hydroxylation activity as indicated by a 0.7-fold decrease in the Km. In the case of metoprolol metabolism, dioxane resulted in a 1.5 to 3.1-fold increase in the Km of all the three metabolite formation pathways in concentration dependent manner, with less marked effect on Vmax of the reaction. Interestingly, while acetonitrile did not affect the Km for metabolite 1 and 2 formation, the Km of metabolite 3 formation was decreased in a concentration dependent manner again with little effect on all the three Vmax values. Further, methanol had little to no effect on the Vmax of metabolite 1 and 2 formation while metabolite 3 formation was increased by 2-fold. The Km of all three metabolite formations was found to be decreased in presence of methanol. The phenacetin deethylation activity in rat liver microsomes followed atypical kinetics. Methanol and dimethyl sulphoxide did not affect the auto activation kinetics at concentration range studied. Dimethyl sulphoxide and dioxane appeared to be unsuitable for characterizing the Cytochrome450 mediated reactions because they showed a very significant effect on the Vmax/Km ratio, starting at concentrations of 0.025 % v/v and 0.25 % v/v, respectively. Methanol and acetonitrile at concentration <0.5 % v/v appeared to be acceptable solvents for solubilization of substrates metabolized by Cytochrome450s.

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.

Effects of water-soluble organic co-solvents on the metabolic kinetics of drugs in rat liver microsomes

The aim of this research was to explore how different water-miscible organic co-solvents, such as methanol, acetonitrile, dimethyl sulphoxide, and dioxane, influence the kinetic characteristics of enzymes in rat liver microsomes that metabolize drugs. Our study revealed that the impact of these co-solvents on enzyme activity was highly dependent on the specific metabolic route involved and the concentration of the co-solvent used. Methanol and dimethyl sulphoxide showed a notable increase in the Km of p-nitrophenol hydroxylation, while acetonitrile showed activation of this metabolic pathway. Interestingly, dioxane resulted in a significant increase in the Km of metoprolol metabolism, while acetonitrile decreased the Km of metabolite 3 formation. In addition, our study findings revealed that the Vmax/Km ratio was significantly affected by dimethyl sulphoxide and dioxane, suggesting their unsuitability for characterizing Cytochrome450 mediated reactions. On the other hand, methanol and acetonitrile were found to be suitable solvents for solubilizing substances that Cytochrome 450s metabolise, as long as their concentration remained below 0.5% v/v. Overall, our study sheds light on the potential effects of chemical co-solvents that are water soluble on enzyme kinetics and highlights the importance of carefully selecting appropriate solvents to study the in vitro metabolism of drugs.

Analyses of serum and urinary metabolites in individuals with peripheral artery disease (PAD) consuming a bean-rich diet: relationships with drug metabolites.

Peripheral artery disease (PAD) has high morbidity and mortality rates. A metabolomics approach was employed to determine whether consumption of bean-rich diets for 8weeks would impact the metabolomic profile of individuals with PAD. Serum and urine, collected from 54 participants with clinical PAD at baseline and after 8weeks on 0.3 cups beans/day (n= 19), 0.6 cups beans/day (n= 20), or control (n= 23) diet, and the beans were extracted and analyzed using LC-QTOF-MS. As a result, PGE2 p-acetamidophenyl ester, PGF2α diethyl amide and 5-l-glutamyl-l-alanine were significantly changed in the serum or urine of bean groups compared with control. Significant changes (P< 0.05) in the profile and/or levels of 22 flavonoids present in bean extracts showed the potential importance of the mixture of beans used in this study. In a subset of participants taking metoprolol, after 8weeks the bean-rich diets significantly elevated metoprolol in the serum while reducing it in urine compared with baseline. In addition, the diets significantly enhanced the urinary excretion of metformin. In conclusion, several biochemical pathways including prostaglandins and glutathione were affected by bean consumption. Significant changes in the metabolism of metoprolol and metformin with bean consumption suggested the presence of diet-drug interactions that may require adjustment of the prescribed dose. ClinicalTrials.gov Identifier: NCT01382056. Novelty: Bean consumption by people with PAD alters the levels of certain metabolites in serum and urine. Different bean types (black, red kidney, pinto, navy) have unique flavonoid profiles. Metabolomics revealed potential diet-drug interactions as serum and/or urinary levels of metoprolol and metformin are modified by bean consumption.

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.

The effect of the CYP2D6 genotype on the maintenance dose of metoprolol in a chronic Dutch patient population.

Metoprolol is among the most frequently prescribed β-blockers for the treatment of various cardiovascular diseases. Genetic polymorphism within CYP2D6 has been shown to affect the rate of metabolism of metoprolol. Whether metoprolol dose adjustments are indicated in CYP2D6 poor metabolizers (PMs) has thus far not well been studied. The aim of this study was to determine the effect of the CYP2D6 genotype on the metoprolol maintenance dose in a chronic Dutch patient population. Patients were included if they were treated with metoprolol and in whom CYP2D6 genotype status was known. Patient and treatment characteristics were obtained retrospectively from the electronic healthcare records. Metoprolol maintenance dose was the primary endpoint and was defined as the last known dose that the patients had been treated with. Genotype data were categorized into four phenotypes, that is, PMs, intermediate metabolizers, extensive metabolizers, and ultra-rapid metabolizers (UMs). The endpoints were analyzed as PM versus non-PM. A total of 105 patients were included. The mean ± SD maintenance dose in PMs (n = 12) was significantly lower compared with non-PMs (n = 93), that is, 48 ± 20 versus 84 ± 53 mg, respectively (P = 0.019). No association of the CYP2D6 genotype with the incidence of side effects was observed, although there was a trend for increased risk of drowsiness (P = 0.053). The results of this study show that the CYP2D6 genotype is associated with the maintenance dose of metoprolol. Patients with the CYP2D6 PM phenotype may benefit from a lower metoprolol starting dose, followed by further dose titration to provide patient-tailored therapy and thereby increase the effectiveness of treatment.

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

Specific study about the effect of cytochrome P450 2D6 (CYP2D6) polymorphisms on the metabolism of clinic drugs is of great significance for drug safety investigation. Here, the interaction between CYP2D6 variants (*1, *2, *10, *39) and metoprolol (MET) was intensively researched in vitro from the aspect of drug-enzyme kinetic study. To obtain quantitative data, α-hydroxymetoprolol (main metabolite of MET) was selected as an ideal analyte and an LC–MS/MS method was adopted for sample determination. Firstly, by selecting suitable internal standard and optimizing separation condition, the LC–MS/MS method was established and validated. Then, the drug-enzyme incubation system was optimized by two parameters: incubation time and amount of enzyme. Lastly, the interaction between CYP2D6 allelic variants and MET was characterized by Km, Vmax and CLint. As a result, four CYP2D6 enzymes displayed diverse Km or Vmax towards MET and the values of CLint showed a wide range from 8.91 to 100%. Relative to CYP2D6*1 (CLint*1 = 100%), CYP2D6*2 demonstrated the second high catalytic activity (CLint*2/*1 = 74.87%) while CYP2D6*39 (CLint*39/*1 = 29.65%) and CYP2D6*10 (CLint*10/*1 = 8.91%) showed minimal catalytic activity. This comprehensive in vitro data suggested the prominent influence of CYP2D6 polymorphisms on the metabolism of MET, which could offer valuable information for personalized administration of MET in clinic.

Effects of CYP2D6*10 on plasma trough concentration of metoprolol in patients with coronary artery disease

To study the effect of CYP2D6*10 (c.100 C&gt;T) on plasma trough concentrations of metoprolol and its metabolite α-hydroxy metoprolol, blood pressure and heart rate in patients with coronary artery disease. The patients with coronary artery disease taking metoprolol tablets (n=128) and those taking metoprolol sustained-release tablets (n=126) were genotyped for CYP2D6*10 using Taqman real-time quantitative PCR. The trough concentrations of metoprolol and α-hydroxy metoprolol were determined with UPLC-MS/MS, and the dose-normalized concentrations (C/D) were compared among the patients with different CYP2D6*10 genotypes in both groups. Resting blood pressure and heart rate were recorded in all the patients when the concentration of metoprolol reached the steady state and were compared among the patients with different genotypes. In patients taking metoprolol sustained-release tablets, the plasma trough concentration of α-hydroxy metoprolol was significantly associated with the systolic blood pressure (P=0.0204). The CYP2D6*10 poor metabolizers showed a significant association with the C/D of metoprolol and α-hydroxy metoprolol (P &lt; 0.01) in patients receiving metoprolol in both formulations, and in both groups, the C/D of metoprolol was significantly higher in the patients with a TT genotype than in those with a CC or CT genotype (P &lt; 0.01); compared with those with the CT genotype, the patients with the TT genotype had a significantly lower C/D of α-hydroxy metoprolol (P &lt; 0.01). In patients taking metoprolol sustained-release tablets, those with the CT (P=0.0281) and TT (P=0.0196) genotypes had lower diastolic blood pressure than patients with the CC genotypes, but the systolic blood pressure or heart rate did not differ significantly among them. CYP2D6*10T allele mutation can reduce the metabolism of metoprolol, increase the C/D of metoprolol and decrease the C/D of α-metoprolol and diastolic blood pressure in patients with coronary artery disease, but CYP2D6*10 variation does not significantly affect systolic blood pressure or heart rate in the patients when the concentration of metoprolol reaches a steady state.

Cytochrome P450 Enzymes Involved in Metoprolol Metabolism and Use of Metoprolol as a CYP2D6 Phenotyping Probe Drug.

Metoprolol is used for phenotyping of cytochrome P450 (CYP) 2D6, a CYP isoform considered not to be inducible by inducers of the CYP2C, CYP2B, and CYP3A families such as rifampicin. While assessing CYP2D6 activity under basal conditions and after pre-treatment with rifampicin in vivo, we surprisingly observed a drop in the metoprolol/α-OH-metoprolol clearance ratio, suggesting CYP2D6 induction. To study this problem, we performed in vitro investigations using HepaRG cells and primary human hepatocytes (before and after treatment with 20 μM rifampicin), human liver microsomes, and CYP3A4-overexpressing supersomes. While mRNA expression levels of CYP3A4 showed a 15- to 30-fold increase in both cell models, mRNA of CYP2D6 was not affected by rifampicin. 1′-OH-midazolam formation (reflecting CYP3A4 activity) increased by a factor of 5–8 in both cell models, while the formation of α-OH-metoprolol increased by a factor of 6 in HepaRG cells and of 1.4 in primary human hepatocytes. Inhibition studies using human liver microsomes showed that CYP3A4, 2B6, and 2C9 together contributed 19.0 ± 2.6% (mean ± 95%CI) to O-demethylation, 4.0 ± 0.7% to α-hydroxylation, and 7.6 ± 1.7% to N-dealkylation of metoprolol. In supersomes overexpressing CYP3A4, metoprolol was α-hydroxylated in a reaction inhibited by the CYP3A4-specific inhibitor ketoconazole, but not by the CYP2D6-specific inhibitor quinidine. We conclude that metoprolol is not exclusively metabolized by CYP2D6. CYP3A4, 2B6, and 2C9, which are inducible by rifampicin, contribute to α-hydroxylation, O-demethylation, and N-dealkylation of metoprolol. This contribution is larger after CYP induction by rifampicin but is too small to compromise the usability of metoprolol α-hydroxylation for CYP2D6 phenotyping.

CYP2D6 Genetic Variation and Beta-Blocker Maintenance Dose in Patients with Heart Failure.

This study examined whether a CYP2D6 polymorphism (CYP2D6*4) was related to beta-blocker maintenance dose in patients with heart failure. Logistic regression modeling was utilized in a retrospective chart-review analysis of heart-failure patients (60% Male, 90% of European descent) to assess whether CYP2D6*4 (non-functional CYP2D6 allele present in 1 of 5 individuals of European descent) is associated with maintenance dose of carvedilol (n = 65) or metoprolol (n = 33). CYP2D6*4 was associated with lower maintenance dose of metoprolol (OR 0.13 [95% CI 0.02-0.75] p = 0.023), and a trend was observed between CYP2D6*4 and higher maintenance dose of carvedilol (OR 2.94 [95% CI 0.84-10.30] p = 0.093). None of the patients that carried CYP2D6*4 achieved the recommended target dose of metoprolol (200mg/day). Consistent with the role of CYP2D6 in the metabolism of metoprolol, the tolerated maintenance dose of metoprolol was lower in CYP2D6*4 carriers compared to non-carriers. Consistent with the role of CYP2D6 in activation of carvedilol, tolerated maintenance dose of carvedilol was higher in CYP2D6*4 carriers compared to non-carriers. Further investigation is warranted to ascertain the potential of CYP2D6 as a potential predictive biomarker of beta-blocker maintenance dose in heart failure patients.

Effect of Dimethoate on the Activity of Hepatic CYP450 Based on Pharmacokinetics of Probe Drugs

Background: Dimethoate (DM), one of the most widely used systemic organophosphate insecticide, has been reported to exert toxic effects after long-time subchronic exposure. This study aims at investigating the toxic effect of DM on liver after repeated administration of low doses of DM in rats. Methods: Twenty Sprague-Dawley rats were randomly divided into the control group (n = 10) and the DM group (n = 10). After 2 weeks' exposure to DM at low dosage (5 mg/kg), biochemical parameters of hepatic functions were measured, histology and CYP450 expressed in liver was detected. The activities of CYP1A2, CYP2C11, CYP2D1, and CYP3A2 were evaluated by the Cocktail method. Results: The level of AChE (acetylcholinesterase) was significantly decreased, hepatic functions were damaged and the mRNA level of CYP2D1 was significantly increased in the DM group (p < 0.05). The pharmacokinetics of probe drug revealed AUC_(0-t), AUC_(0-_∞₎, t_1/2 and C_max of metoprolol was shorten in the DM group (p < 0.05). However, there were no statistical differences in MRT, t_1/2, CL and T_max for phenacetin, tolbutamide and midazolam. Conclusions: A low dosage of DM could induce the activity of CYP2D1 in liver and increase the metabolism of metoprolol when exposed for 2 weeks.

Influence of gestational diabetes on the stereoselective pharmacokinetics and placental distribution of metoprolol and its metabolites in parturients.

To investigate the influence of gestational diabetes mellitus (GDM) on the kinetic disposition and transplacental and amniotic fluid distribution of metoprolol and its metabolites O-desmethylmetoproloic acid and α-hydroxymetoprolol stereoisomers in hypertensive parturients receiving a single dose of the racemic drug. The study was conducted on hypertensive parturients with well-controlled GDM (n = 11) and non-diabetic hypertensive parturients (n = 24), all receiving a single 100 mg oral dose of racemic metoprolol tartrate before delivery. Serial maternal blood samples (0-24 h) and umbilical blood and amniotic fluid samples were collected for the quantitation of metoprolol and its metabolite stereoisomers using LC-MS/MS or fluorescence detection. The kinetic disposition of metoprolol and its metabolites was stereoselective in the diabetic and control groups. Well-controlled GDM prolonged tmax for both enantiomers of metoprolol (1.5 vs. 2.5 h R-(+)-MET; 1.5 vs. 2.75 h S-(-)-MET) and O-desmethylmetoproloic acid (2.0 vs. 3.5 h R-(+)-AOMD; 2.0 vs. 3.0 h S-(-)-OAMD), and for the four stereoisomers of α-hydroxymetoprolol (2.0 vs. 3.0 h for 1'S,2R-, 1'R,2R- and 1'R,2S-OHM; 2.0 vs. 3.5 h for 1'S,2S-OHM) and reduced the transplacental distribution of 1'S,2S-, 1'R,2R-, and 1'R,2S-OHM by approximately 20%. The kinetic disposition of metoprolol was enantioselective, with plasma accumulation of the S-(-)-MET eutomer. Well-controlled GDM prolonged the tmax of metoprolol and O-desmethylmetoproloic acid enantiomers and the α-hydroxymetoprolol stereoisomers and reduced by about 20% the transplacental distribution of 1'S,2S-, 1'R,2R-, and 1'R,2S-OHM. Thus, well-controlled GDM did not change the activity of CYP2D6 and CYP3A involved in metoprolol metabolism.

Effect of Water-miscible Organic Solvents on CYP450-mediated Metoprolol and Imipramine Metabolism in Rat Liver Microsomes.

The catalytic activity of cytochrome P450 enzymes is known to be affected by presence of organic solvents in in vitro assays. However, these effects tend to be variable and depend on the substrate and CYP450 isoform in question. In the present study, we have investigated effect of ten water miscible organic solvents (methanol, ethanol, propanol, isopropanol, acetone, acetonitrile, dimethylsulphoxide, dimethylformamide, dioxane and PEG400) on water soluble substrates of CYP450, metoprolol and imipramine, at 0, 0.1, 0.25, 0.5, 0.75 and 1% v/v concentration in rat liver microsomes. Organic solvents studied had a concentration dependent inhibitory effect on the metoprolol and imipramine metabolism activity. Metoprolol metabolism was found to be more susceptible to the organic solvents, almost all the ten solvents had more or less inhibitory effect compared to imipramine metabolism. Except acetone, PEG400 and dimethylsulphoxide, all solvents had ~50% inhibition of total metoprolol metabolism activity, while in case of imipramine metabolism activity, only n-propanol, isopropanol and PEG400 had ~50% inhibition at 1% v/v. Interestingly, methanol, dimethylsulphoxide and acetonitrile had negligible effect on the imipramine metabolism (less than 10% inhibition at 1% v/v) while, total metoprolol metabolism activity was substantially inhibited by these solvents (MeOH 52%, DMSO 29% and ACN 47% at 1% v/v). In both cases, dioxane was found to be the most inhibitory solvent (~90% inhibition at 1% v/v).

Possibility of Decrease in CYP1A2 Function in Patients With End‐Stage Renal Disease

Propranolol, the substrate of cytochrome P450 (CYP) 1A2 and CYP2D6, has been reported to be in high concentrations in end-stage renal disease (ESRD) patients. This has been thought to be due to the decrease in the nonrenal clearance of propranolol. The objective of this study is to elucidate the reason for the decrease in nonrenal clearance in ESRD patients. CYP1A2 and CYP2D6 activities were estimated by the phenacetin O-deethylation and methoprolol O-demethylation methods, respectively. Pooled normal serum and pooled uremic serum were deproteinized by methanol in order to exclude high-molecular-weight compounds. We selected as candidate inhibitors: uremic toxins such as 3-indoxyl sulfate, 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid, indole-3-acetic acid, and hippuric acid, and xanthine derivatives such as allantoin, uric acid, and xanthine. In this study, uremic serum was found to inhibit the CYP1A2-mediated metabolism of phenacetin to acetaminophen in a concentration-dependent and competitive manner. Xanthine also inhibited the metabolism of CYP1A2. On the other hand, uremic serum and the four uremic toxins did not inhibit the CYP2D6-mediated metabolism of metoprolol to O-demethylmetoprolol. In conclusion, this study suggests that the increase of the bioavailability of propranolol in ESRD is partly induced by the inhibition of the hepatic metabolism of CYP1A2 by xanthine in the uremic serum.

Faster non-renal clearance of metoprolol in streptozotocin-induced diabetes mellitus rats

Metoprolol is a selective β1-adrenergic receptor antagonist metabolized by hepatic cytochrome P450s (CYPs). In this study, we evaluated pharmacokinetic changes following intravenous (i.v.) and oral metoprolol in rats with diabetes mellitus induced by streptozotocin (DMIS). Metoprolol has an intermediate hepatic extraction ratio in rats (0.586–0.617), and it is assumed that the liver is exclusively responsible for metoprolol metabolism. Thus, the hepatic clearance, CLH (the non-renal clearance, CLNR) of metoprolol depends on the hepatic blood flow rate (QH), the free fraction in plasma (fp), and in vitro hepatic intrinsic clearance, CLint. After i.v. administration of 1.5mg/kg metoprolol to DMIS rats, its CLNR was 40.9% faster than control animals. This could be due to a significantly faster QH because hepatic CLint and fp were comparable between the two groups of rats due to unchanged hepatic CYP2D activity. After oral administration of 1.5mg/kg metoprolol to DMIS rats, gastrointestinal absorption was >99% of the oral dose for both groups, while the area under the curve (AUC) was 27.9% smaller, which could be caused by the greater hepatic metabolism seen in the i.v. study. These findings have potential therapeutic implications, assuming that the DMIS rats qualitatively reflect similar changes in patients with diabetes.

A Meta-Analysis of CYP2D6 Metabolizer Phenotype and Metoprolol Pharmacokinetics

Metoprolol, a commonly prescribed beta-blocker, is primarily metabolized by cytochrome P450 2D6 (CYP2D6), an enzyme with substantial genetic heterogeneity. Several smaller studies have shown that metoprolol pharmacokinetics is influenced by CYP2D6 genotype and metabolizer phenotype. To increase robustness of metoprolol pharmacokinetic estimates, a systematic review and meta-analysis of pharmacokinetic studies that administered a single oral dose of immediate release metoprolol was performed. Pooled analysis (n= 264) demonstrated differences in peak plasma metoprolol concentration, area under the concentration-time curve, elimination half-life, and apparent oral clearance that were 2.3-, 4.9-, 2.3-, and 5.9-fold between extensive and poor metabolizers, respectively, and 5.3-, 13-, 2.6-, and 15-fold between ultra-rapid and poor metabolizers (all p<0.001). Enantiomer-specific analysis revealed genotype-dependent enantio-selective metabolism, with nearly 40% greater R- vs S-metoprolol metabolism in ultra-rapid and extensive metabolizers. This study demonstrates a marked effect of CYP2D6 metabolizer phenotype on metoprolol pharmacokinetics and confirms enantiomer specific metabolism of metoprolol.

Pharmacokinetic interaction between metoprolol and SP-8203 in rats: competitive inhibition for the metabolism of metoprolol by SP-8203 via hepatic CYP2D subfamily

The occurrence of cerebral ischemia is prevalent in patients with hypertension and the combination drug therapy is needed. Thus, the pharmacokinetic interaction between metoprolol (anti-hypertension drug) and SP-8203 (a new drug candidate for cerebral ischemia) with respect to the metabolism via CYP isozymes was evaluated.Metoprolol and SP-8203 were administered intravenously or orally to rats. Concentrations (I) of each drug in the liver and intestine in in vivo studies, the disappearance and apparent Ki of each drug in in vitro microsomes and [I]/Ki ratios for each drug were determined. In addition, the disappearance of each drug via CYPs in rat and human microsomes were measured.The AUC and CLNR of intravenously administered metoprolol with SP-8203 were significantly greater and slower, respectively, than without SP-8203. However, pharmacokinetic parameters of oral metoprolol and intravenous/oral SP-8203 were not altered.The hepatic metabolism of metoprolol via CYP2D was inhibited by SP-8203 in a competitive manner. However, the intestinal metabolism of metoprolol was not influenced by SP-8203. SP-8203 was not metabolized via CYP isozymes in rats and then co-administration of metoprolol did not affect the metabolism of SP-8203.