Tolbutamide

Synthetic Routes and Reaction Conditions: Tolbutamide can be synthesized through the reaction of p-toluene sulfonamide with butyl isocyanate in the presence of triethylamine and tetrahydrofuran . Another method involves dissolving a specified carbamate derivative in hot toluene, adding butylamine slowly, and refluxing for four hours .

Industrial Production Methods: In industrial settings, this compound particles can be prepared by mixing the bulk drug with a supercritical fluid to form a supercritical mixture, which is then expanded to obtain the this compound particles . This method is particularly useful for producing this compound micro-particles.

Types of Reactions: Tolbutamide undergoes various chemical reactions, including oxidation, reduction, and substitution reactions.

Common Reagents and Conditions:

Oxidation: this compound can be oxidized using strong oxidizing agents.

Reduction: Reduction reactions typically involve the use of reducing agents like lithium aluminum hydride.

Substitution: Substitution reactions can occur in the presence of nucleophiles or electrophiles under appropriate conditions.

Major Products: The major products formed from these reactions depend on the specific reagents and conditions used. For example, oxidation may yield sulfonic acid derivatives, while reduction could produce amine derivatives.

Clinical Applications

• Management of Type 2 Diabetes Mellitus :
  • Tolbutamide is primarily prescribed for patients with non-insulin-dependent diabetes mellitus (NIDDM). It is often used in conjunction with dietary modifications to improve glycemic control .
  • A study involving 1,030 diabetic patients highlighted that this compound effectively maintained glycemic control in those with a lower insulin requirement and later-onset diabetes .
• Research Applications :
  • Animal Studies : Research has shown that this compound can reduce the incidence of diabetes in non-obese diabetic mice. In one study, treatment with this compound significantly decreased the cumulative incidence of diabetes compared to controls .
  • Insulin Release Studies : Investigations into the effects of this compound on insulin release from isolated rat islets demonstrated that it stimulates insulin secretion in a dose-dependent manner, particularly at low glucose concentrations .
• Pharmacogenetics and Adverse Drug Reactions :
  • The pharmacogenetic profile of patients can influence the efficacy and safety of this compound. Genetic variations affecting drug metabolism may lead to adverse reactions or altered drug effectiveness, particularly in elderly populations .

Case Studies

• Long-term Use and Efficacy : A long-term study indicated that this compound was effective in maintaining blood glucose levels in a significant number of patients over extended periods. Factors such as age at onset and insulin requirements were identified as critical determinants of treatment success .
• Comparative Effectiveness : In comparative studies against other antidiabetic agents, this compound has been shown to have a favorable profile concerning weight gain and hypoglycemia risk compared to newer agents like GLP-1 receptor agonists .

Data Table: Summary of Clinical Findings

トルブタミドは、膵臓のβ細胞からインスリンの放出を促進することで、血糖降下作用を発揮します。 β細胞のATP感受性カリウムチャネルに結合して阻害することで、細胞の脱分極を引き起こし、その後のインスリン放出につながります . さらに、トルブタミドは肝臓からのグルコース産出を抑制し、末梢標的部位におけるインスリン感受性を高めます .

トルブタミドは、アセトヘキサミド、クロルプロパミド、トラザミドなどの他の化合物を含む、スルホニルウレア系のインスリン分泌促進剤に属します . これらの化合物と比較して、トルブタミドは作用時間が短く、副作用の発生率が高いです . トルブタミドは、作用発現が速く、インスリン放出を促進する効果が高いため、糖尿病管理において依然として貴重なツールです。

類似化合物：

• アセトヘキサミド
• クロルプロパミド
• トラザミド

トルブタミドのユニークな点は、代謝が速く、作用時間が短いことです。このため、高齢者での使用に適しています .

Tolbutamide is a first-generation sulfonylurea commonly used in the management of type 2 diabetes mellitus. Its primary mechanism of action involves stimulating insulin release from pancreatic β-cells, thereby lowering blood glucose levels. This article delves into the biological activity of this compound, supported by various studies and case analyses.

This compound operates by inhibiting ATP-sensitive potassium (K$_{ATP}$) channels in pancreatic β-cells. This inhibition causes depolarization of the cell membrane, leading to the opening of voltage-dependent calcium channels and an influx of calcium ions, which triggers insulin secretion. The effects are dose-dependent and vary with glucose concentrations.

• At low glucose levels (75 mg/dl), this compound enhances insulin release in a dose-dependent manner, but high concentrations can lead to a monophasic release pattern due to prolonged depolarization that inactivates calcium channels .
• In contrast, at higher glucose levels (150 mg/dl), this compound can reduce the insulin-releasing effect of glucose, indicating a complex interaction between these substances .

Pharmacokinetics and Interactions

Recent studies have highlighted interactions between this compound and other substances, such as pomegranate juice (PJ). The combination of PJ and this compound significantly improved outcomes in diabetic complications compared to this compound alone. The pharmacokinetic profile showed that PJ enhances the bioavailability and half-life of this compound while reducing its clearance .

Efficacy in Clinical Trials

A comparative study involving glipizide and this compound demonstrated that while both drugs effectively lower fasting serum glucose levels, glipizide showed superior results in terms of postprandial glucose control and insulin secretion during therapy . Specifically, glipizide resulted in a 25% reduction in fasting glucose compared to 17% with this compound over six months.

Case Studies

• University Group Diabetes Program (UGDP) :
  • A landmark trial assessed the long-term effects of this compound on cardiovascular complications in diabetes patients. The study concluded that this compound was ineffective and potentially harmful, leading to its decreased usage over time .
• Hypoglycemia Diagnostic Test :
  • A study involving intravenous sodium this compound demonstrated fluctuating blood sugar levels in patients with hypoglycemia and pancreatic hyperinsulinism, showcasing its diagnostic potential beyond therapeutic use .

Effects on Glucose Metabolism

This compound has been shown to alter glucose transport and metabolism across various tissues:

• In embryonic heart tissues, exposure to this compound increased glucose uptake and glycolysis while upregulating glucose transporter proteins (GLUT-1) and hexokinase I (HKI) levels .
• This suggests that this compound not only affects pancreatic function but also has significant impacts on peripheral tissues involved in glucose metabolism.

Summary of Research Findings

Basic Research Question

Q. Q1. What experimental approaches are recommended to elucidate Tolbutamide’s mechanism of action in pancreatic β-cells?

Methodological Answer:

• Step 1 : Use in vitro electrophysiology (e.g., patch-clamp techniques) to confirm this compound’s binding to sulfonylurea receptor 1 (SUR1) and subsequent ATP-sensitive potassium (K$_\text{ATP}$) channel inhibition .
• Step 2 : Measure insulin secretion in isolated islets via ELISA under varying glucose concentrations to correlate channel inhibition with hormonal output.
• Step 3 : Validate findings in animal models (e.g., streptozotocin-induced diabetic rats) to assess glucose-lowering efficacy and tissue specificity .

Basic Research Question

Q. Q2. How does CYP2C9 polymorphism influence this compound pharmacokinetics, and what experimental designs address this variability?

Methodological Answer:

• Approach : Conduct in vitro metabolism assays using recombinant CYP2C9 isoforms (e.g., CYP2C92 and CYP2C93) to quantify 4-hydroxythis compound formation rates .
• Clinical Validation : Perform pharmacokinetic studies in genotyped cohorts, measuring plasma concentration-time profiles (AUC, C$_\text{max}$, t$_{1/2}$) using HPLC-UV (mobile phase: 10 mM sodium acetate buffer [pH 4.4]/acetonitrile, 25:75 v/v) .
• Statistical Analysis : Apply ANOVA to compare metabolic clearance between genotypes, adjusting for covariates like age and liver function .

Advanced Research Question

Q. Q3. How can physiologically based pharmacokinetic (PBPK) modeling resolve contradictions in this compound-drug interaction studies?

Methodological Answer:

• Model Development : Integrate in vitro CYP2C9 inhibition constants (K$_\text{i}$) and clinical PK data into software (e.g., Simcyp®) to simulate this compound exposure with inhibitors (e.g., sulfaphenazole) .
• Verification : Compare simulated AUC ratios (e.g., 2.5–3.5-fold increase with sulfaphenazole) against clinical observations to validate model accuracy .
• Application : Predict interactions with novel CYP2C9 inhibitors (e.g., tasisulam) to guide dose adjustments in cancer patients .

Advanced Research Question

Q. Q4. How should researchers address contradictory efficacy data for this compound across patient subpopulations?

Methodological Answer:

• Meta-Analysis : Pool data from RCTs (e.g., 53-patient cohorts ) to stratify outcomes by covariates (age, BMI, prior insulin use).
• Confounder Adjustment : Use multivariate regression to isolate this compound’s effect from dietary adherence or comorbid conditions .
• In Silico Screening : Apply machine learning to EHR datasets to identify subpopulations with optimal HbA1c reduction .

Q. Methodological Guidance

Q. Q5. What quality control measures ensure reproducibility in this compound batch preparation for preclinical studies?

Methodological Answer:

• Analytical QC :
  • HPLC-UV : Monitor purity (>98%) and stability under storage conditions (e.g., 4°C vs. room temperature) .
  • Mass Spectrometry : Confirm molecular identity (m/z 271.2 for this compound; m/z 287.2 for 4-hydroxythis compound) .
• Batch Consistency :
  • Table 1 : Example QC Parameters

Advanced Research Question

Q. Q6. How can researchers reconcile in vitro CYP2C9 inhibition data with in vivo this compound interaction outcomes?

Methodological Answer:

• Step 1 : Measure unbound inhibitor concentrations in vivo to adjust in vitro K$_\text{i}$ values for protein binding .
• Step 2 : Use static models (e.g., [I]/K$_\text{i}$ >0.1 threshold) to predict clinical relevance of in vitro findings .
• Step 3 : Validate with dynamic PBPK models incorporating hepatic blood flow and enzyme saturation .

Basic Research Question

Q. Q7. What criteria should guide patient selection for this compound trials to minimize confounding variables?

Methodological Answer:

• Inclusion Criteria :
  • Mild type 2 diabetes (HbA1c 6.5–8.0%) .
  • Naïve to insulin therapy, responsive to dietary control .
• Exclusion Criteria :
  • Hepatic impairment (alters CYP2C9 activity) .
  • Concomitant CYP2C9 inhibitors/inducers .