Glipizide

Pancreatic Beta-Cell Sulfonylurea Receptor (SUR1) Binding Dynamics

The principal mechanism by which glipizide stimulates insulin release involves its interaction with specific receptors on the pancreatic beta-cell plasma membrane. This compound binds to the sulfonylurea receptor 1 (SUR1), which is a regulatory subunit of the ATP-sensitive potassium (KATP) channel complex drugbank.comnih.govclinicalcorrelations.orgacs.orgresearchgate.net. This binding is crucial for initiating the cascade of events leading to insulin secretion drugbank.comnih.govclinicalcorrelations.orgpatsnap.com.

Upon binding to the SUR1 subunit, this compound causes the closure of the ATP-sensitive potassium (KATP) channels in the pancreatic beta-cell membrane drugbank.comnih.govclinicalcorrelations.orgacs.orgresearchgate.netpatsnap.comnih.gov. In a resting state, these KATP channels permit the efflux of potassium ions (K+) from the beta-cell, maintaining a hyperpolarized membrane potential nih.govpatsnap.complos.orgdiabetesjournals.org. The inhibition of K+ efflux by this compound leads to a reduction in potassium conductance across the membrane drugbank.com. This closure of KATP channels is a pivotal step, as it directly alters the ion flux and sets the stage for membrane depolarization drugbank.comnih.govclinicalcorrelations.orgacs.orgresearchgate.netpatsnap.com.

The reduced potassium efflux resulting from KATP channel closure leads to the accumulation of positive charges inside the pancreatic beta-cell, causing depolarization of the cell membrane drugbank.comnih.govclinicalcorrelations.orgacs.orgresearchgate.netpatsnap.comnih.gov. This depolarization is a critical event, as it triggers the opening of voltage-gated calcium (Ca2+) channels embedded in the beta-cell membrane drugbank.comnih.govclinicalcorrelations.orgacs.orgresearchgate.netpatsnap.comnih.gov. The opening of these channels facilitates a rapid influx of calcium ions into the intracellular space drugbank.comnih.govclinicalcorrelations.orgacs.orgresearchgate.netpatsnap.comnih.gov.

The increase in intracellular calcium ion concentrations, resulting from the influx through voltage-gated calcium channels, is the direct stimulus for insulin secretion drugbank.comnih.govpatsnap.comnih.govpatsnap.com. Elevated cytosolic Ca2+ levels trigger the contraction of actomyosin filaments, which in turn stimulates the exocytosis of insulin-containing secretory granules from the pancreatic beta-cells into the bloodstream drugbank.comnih.govpatsnap.compatsnap.comdrugbank.com. This process enhances the release of endogenous insulin, thereby contributing to the reduction of blood glucose levels drugbank.compatsnap.comnih.govpatsnap.comwikipedia.org.

Extrapancreatic Effects of this compound

This compound has been shown to enhance peripheral insulin sensitivity nih.govwikipedia.orgfda.govtsijournals.commims.comsquarepharma.com.bdmims.com. This effect may involve an increase in the number and sensitivity of insulin receptors on peripheral target cells, such as muscle and adipose tissue cells drugbank.comclinicalcorrelations.orgnih.govtsijournals.com. By improving the responsiveness of these tissues to insulin, this compound facilitates increased glucose uptake and utilization by peripheral cells, thereby contributing to lower blood glucose concentrations drugbank.compatsnap.comdrugbank.comtsijournals.com. Studies have indicated that patients who exhibit a prolonged response to this compound often demonstrate increased insulin sensitivity tsijournals.com.

Another important extrapancreatic effect of this compound is the inhibition of hepatic glucose production drugbank.compatsnap.comnih.govwikipedia.orgfda.govtsijournals.commims.comsquarepharma.com.bdmims.com. This involves a reduction in both gluconeogenesis and glycogenolysis in the liver drugbank.com. By decreasing the output of glucose from the liver, this compound directly contributes to the lowering of fasting and postprandial blood glucose levels drugbank.compatsnap.comnih.govwikipedia.orgfda.govtsijournals.commims.comsquarepharma.com.bdmims.com. This effect, combined with enhanced peripheral glucose utilization, underscores the multifaceted approach of this compound in glycemic control.

Absorption and Bioavailability Studies

The absorption and bioavailability of glipizide are critical determinants of its therapeutic action, influencing the onset and duration of its glucose-lowering effects.

Distribution Parameters

Following absorption, this compound is distributed throughout the body, with its distribution characteristics significantly influenced by its protein binding affinity and apparent volume of distribution.

Metabolism and Biotransformation Pathways

The metabolic transformation of this compound is extensive and primarily occurs in the liver. hpra.iedrugs.compfizer.commedsinfo.com.au Hepatic biotransformation is the predominant route of elimination for the compound. drugbank.com

Excretion and Elimination Kinetics

This compound and its metabolites are primarily eliminated from the body through both renal (urine) and fecal routes. medcentral.com

Pharmacokinetic Drug-Drug Interactions

Pharmacokinetic interactions alter the concentration of glipizide in the body, primarily by affecting its metabolism, protein binding, or clearance.

This compound undergoes extensive hepatic biotransformation, with its metabolism primarily mediated by the cytochrome P450 isoenzyme CYP2C9, and to a lesser extent, by CYP2C19 nih.gov. This metabolic pathway converts this compound into inactive hydroxylated metabolites (3-cis-hydroxythis compound and 4-trans-hydroxythis compound) nih.gov. Consequently, co-administration with drugs that inhibit or induce CYP2C9 can significantly alter this compound plasma concentrations and, by extension, its pharmacological effects.

CYP2C9 Inhibitors: Inhibitors of CYP2C9 can decrease the metabolism of this compound, leading to increased plasma concentrations of the active drug and a heightened risk of hypoglycemia nih.govmedscape.comefda.gov.etresearchgate.netnih.gov.

Table 1: Examples of CYP2C9 Inhibitors and Their Impact on this compound Metabolism

CYP2C9 Inducers: Conversely, drugs that induce CYP2C9 activity can accelerate this compound metabolism, potentially leading to decreased this compound plasma concentrations and a reduction in its hypoglycemic effect, which may result in a loss of glycemic control.

Table 2: Examples of CYP2C9 Inducers and Their Potential Impact on this compound Metabolism

This compound is highly bound to plasma proteins, with approximately 99% of the drug circulating in a protein-bound state nih.gov. The unbound fraction is pharmacologically active. Co-administration with other highly protein-bound drugs can lead to competitive displacement of this compound from its binding sites, increasing the concentration of free this compound in the plasma. This increase in free drug can potentiate this compound's hypoglycemic action, elevating the risk of hypoglycemia medscape.comgoodrx.com.

Table 3: Examples of Drugs Affecting this compound Protein Binding

Table 4: Examples of Medications Affecting this compound Clearance/Absorption

Pharmacodynamic Drug-Drug Interactions

Pharmacodynamic interactions occur when drugs have additive, synergistic, or antagonistic effects on the same physiological system, in this case, glucose regulation.

Combining this compound with other antidiabetic agents can lead to synergistic effects, enhancing glucose lowering and increasing the risk of hypoglycemia.

Table 5: Synergistic Hypoglycemic Interactions with Other Antidiabetic Agents

Conversely, certain medications can antagonize the hypoglycemic effects of this compound, leading to elevated blood glucose levels and a potential loss of glycemic control.

Table 6: Antagonistic Effects Leading to Hyperglycemia

Drug-Food Interactions

Food intake can influence the pharmacokinetic profile of this compound, particularly its absorption characteristics.

Effect of Food on this compound Absorption: The absorption of this compound can be delayed by the presence of food wikipedia.orgwikipedia.orgmims.comwikidata.orgmims.commims.com. For immediate-release this compound formulations, food intake can delay absorption by approximately 0.5 hours wikipedia.orgmims.com. Despite this delay, the total systemic absorption (bioavailability) of immediate-release this compound generally remains unaffected by food wikipedia.orgwikipedia.orgmims.com.

Conversely, for immediate-release this compound, research indicates that taking the drug 0.5 hours before a meal leads to an earlier increase in plasma insulin levels and a more pronounced reduction in blood glucose compared to taking it concurrently with breakfast wikipedia.org. This suggests that pre-meal administration of immediate-release this compound optimizes the relationship between drug concentration and the metabolic demands of a meal, promoting more effective insulin release and glucose disposition wikipedia.org.

Summary of Food Effects on this compound Pharmacokinetics:

Quantification in Biological Matrices (Plasma, Urine, Saliva)

Quantifying Glipizide in biological matrices such as plasma, urine, and saliva is vital for understanding its pharmacokinetics, bioavailability, and bioequivalence. Biological matrices are complex mixtures containing numerous endogenous compounds that can interfere with the analysis of target analytes. Therefore, sample preparation techniques, such as protein precipitation or liquid-liquid extraction, are often employed to isolate this compound from these interferences before chromatographic or electrophoretic analysis. oup.comnih.govresearchgate.netwisdomlib.org

For instance, a simple one-step protein precipitation with methanol has been effectively used for preparing human plasma samples for this compound quantification via Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS/MS). oup.comnih.gov Similarly, liquid-liquid extraction with toluene has been reported for the extraction of this compound from human plasma samples prior to High-Performance Liquid Chromatography (HPLC) analysis. nih.gov In urine, solid-phase extraction has been utilized to prepare samples for capillary electrophoresis (CE) analysis of this compound and its metabolites. nih.gov

Chromatographic Techniques and Advancements

Chromatographic techniques are widely employed for the separation and quantification of this compound due to their high resolving power and sensitivity.

HPLC with UV detection is a common and well-established method for this compound analysis in both pharmaceutical formulations and biological samples. nih.govresearchgate.netaustinpublishinggroup.comaustinpublishinggroup.comnih.gov This technique offers good sensitivity, selectivity, and reproducibility.

Detailed Research Findings and Methodologies:

Human Plasma Analysis: A simple, sensitive, and selective reversed-phase HPLC (RP-HPLC) method with UV detection at 275 nm has been developed for this compound determination in human plasma. The method utilized a C18 column (ZORBAX ODS 4.6 × 150 mm) and a mobile phase composed of 0.01 M potassium dihydrogen phosphate and acetonitrile (65:35, v/v) adjusted to pH 4.25 with glacial acetic acid. Liquid-liquid extraction was used for sample preparation. This method demonstrated linearity over a concentration range of 50–1600 ng/mL, with a limit of quantification (LOQ) of 50 ng/mL and mean recovery above 98%. nih.govresearchgate.netnih.gov

Pharmaceutical Samples: Another RP-HPLC method for this compound quantification in pharmaceutical samples employed an Inertsil ODS 3V (150 × 4.6 mm; 5 µm particle size) column with an isocratic mobile phase of 10 mM potassium dihydrogen phosphate (pH 3.9) and methanol (60:40 v/v). Detection was performed at 220 nm. This method showed linearity from 1–450 µg/mL, with a limit of detection (LOD) of 0.03 µg/mL and LOQ of 0.09 µg/mL. austinpublishinggroup.comaustinpublishinggroup.com

Table 1: Representative HPLC-UV Method Parameters for this compound Quantification

LC-MS/MS offers enhanced sensitivity and selectivity compared to UV detection, making it particularly suitable for bioanalytical applications where low concentrations of this compound need to be quantified in complex biological matrices. oup.comresearchgate.netrjptonline.orgnih.gov

Detailed Research Findings and Methodologies:

Rat Plasma Analysis: An LC-MS method was developed for the rapid quantitative estimation of this compound and Sitagliptin in rat plasma. The chromatographic conditions involved an isocratic mode using a Waters X-Bridge C18 3.5µ (150x4.6mm) column. The mobile phase consisted of 0.1% orthophosphoric acid and Acetonitrile in an 80:20 ratio. Detection was performed in positive electrospray ionization (ESI) mode using MS. The method showed linearity for this compound in the range of 10-150 ng/mL, with a recovery of 99.5%. rjptonline.org

Human Urine Analysis (Metabolites): An LC-MS/MS method was developed for the simultaneous quantification of this compound and its four hydroxylated metabolites in human urine. Sample preparation involved protein precipitation with methanol. Analytes were separated on a reversed-phase column with a mobile phase of 0.1% formic acid in acetonitrile and 0.1% formic acid in water using gradient elution. This method could measure amounts as small as 1 ng/mL, with mean recovery of this compound added to plasma ranging from 99-105% over 1-500 ng/mL. researchgate.net

Serum Analysis for Hypoglycemia Cases: A qualitative LC-MS/MS assay was developed for the rapid identification of sulfonylureas, including this compound, in serum. The method used an Agilent HPLC with an AB Sciex 3200 LC-MS/MS operating in ESI positive mode. The method showed a correlation coefficient of 0.99 for this compound. nih.gov

Table 2: Representative LC-MS/MS Method Parameters for this compound Quantification

UPLC-MS/MS offers significant advantages over conventional HPLC, including faster analysis times, improved resolution, and enhanced sensitivity due to smaller particle sizes in columns and higher operating pressures. oup.comnih.gov

Detailed Research Findings and Methodologies:

A rapid, sensitive, and selective UPLC-MS/MS method was developed for the determination of this compound in human plasma, using carbamazepine as the internal standard. Sample preparation involved simple protein precipitation with methanol. Chromatographic separation was performed on an Acquity BEH C18 column (2.1 mm × 50 mm, 1.7 μm) with a gradient profile at a flow rate of 0.4 mL/min. Mass spectrometric analysis used a QTrap5500 mass spectrometer with an electrospray ionization source in positive ion mode. Multiple reaction monitoring (MRM) transitions of m/z 446.1 → 321.0 for this compound and m/z 237.1 → 194.2 for the internal standard were used. The method was linear within the concentration range of 10–1500 ng/mL, with an analytical run time of only 1.0 min. oup.comnih.gov

UPLC with PDA and HRMS detection has also been used for impurity identification and forced degradation studies of this compound, allowing for rapid identification and confirmation of degradation products.

Table 3: Representative UPLC-MS/MS Method Parameters for this compound Quantification

Capillary Electrophoresis (CE) and its variant, Micellar Electrokinetic Chromatography (MEKC), have been explored for the analysis of sulfonylurea drugs, including this compound. nih.govresearchgate.netnih.govjcsp.org.pk CE offers advantages such as low sample and reagent consumption, high separation efficiency, and rapid analysis times.

Detailed Research Findings and Methodologies:

MEKC in tandem with diode array detection (DAD) has been utilized for the separation and detection of sulfonylurea drugs and their metabolites in urine. A separation buffer consisting of 5 mM borate/5 mM phosphate/75 mM sodium cholate allowed for the separation of this compound. While parent compounds were difficult to detect in urine, metabolites were successfully detected using DAD, with peak intensities correlating with dose and time. nih.gov

Another study evaluated CE as a quantitative method for this compound in serum, following solid-phase extraction (SPE) purification. The analysis was performed using micellar electrokinetic capillary chromatography in a buffer containing 5 mmol/L borate, 5 mmol/L phosphate, 75 mmol/L sodium cholate, pH 8.5, and 25 mL/L methanol. Separation was achieved in a 20 cm x 50 µm (i.d.) silica capillary at 25°C and +10 kV. This method demonstrated good linearity (r² ≥0.998) and recovery (≥80%) for this compound. nih.gov

Gas Chromatography (GC) has also been reported for the determination of this compound, particularly for the analysis of residual solvents in this compound active pharmaceutical ingredients (APIs). rjptonline.orgrroij.comresearchgate.net While GC can be used for this compound analysis, it often requires derivatization to make the compound volatile and thermally stable, which can be time-consuming and may lack specificity for structurally similar sulfonylureas. nih.govsphinxsai.com

Detailed Research Findings and Methodologies:

A headspace gas chromatography (HSGC) method with a flame ionization detector (FID) was developed for the quantification of residual solvents (e.g., methanol, acetone, dimethyl formamide, ethylene dichloride) in this compound. This method utilized a DB-Wax 0.25mm, 0.3µm column with nitrogen as a carrier gas and a thermostat temperature of 115 °C for 40 minutes per vial. The method showed good linearity (R² > 0.99) and precision. rjptonline.orgrroij.comresearchgate.net

Earlier reports mentioned electron-capture gas chromatography for plasma sulfonylureas after extractive methylation, determining this compound derivatives up to about 20 ng/mL in plasma samples. sphinxsai.com

Table 4: Representative GC Method Parameters for Residual Solvents in this compound

Comparisons with Other Antidiabetic Drug Classes (e.g., Metformin, DPP-4 Inhibitors, Thiazolidinediones)

Development of Extended-Release and Controlled-Release Formulations

The development of novel Glipizide formulations aims to prolong its therapeutic effect and optimize its pharmacokinetic profile. Various advanced drug delivery systems have been explored to achieve sustained and controlled release.

Pharmacokinetic and Pharmacodynamic Advantages of Novel Formulations

Novel this compound formulations offer significant pharmacokinetic and pharmacodynamic advantages over conventional immediate-release forms.

From a pharmacokinetic perspective, extended-release formulations like this compound GITS provide more stable plasma drug concentrations, reducing the pronounced peak concentrations observed with immediate-release this compound. scielo.brresearchgate.netpfizer.compfizer.com This leads to a more consistent drug exposure over the 24-hour dosing interval. pfizer.compfizer.com For instance, the mean Cmax after immediate-release this compound was significantly greater than after this compound GITS, while the mean Cmin with this compound GITS was approximately 80% higher than with immediate-release this compound. scielo.br Although the mean AUC 0-24 was lower with this compound GITS in some short-term studies, the GITS formulation maintained similar effects on serum glucose, insulin, and C-peptide concentrations. scielo.br This absence of a pronounced peak plasma concentration can be advantageous in maintaining clinical effectiveness. scielo.br The absolute bioavailability of this compound is nearly 100% following oral administration of immediate-release forms, and extended-release tablets gradually reach maximum concentrations within 6 to 12 hours. phmethods.net Sustained-release formulations aim to optimize drug absorption by ensuring controlled and gradual release over time, potentially improving bioavailability by extending drug presence in systemic circulation. bioresscientia.com

Table 3: Pharmacokinetic and Pharmacodynamic Advantages of Novel this compound Formulations

Formulation Challenges and Strategies for this compound

This compound is categorized as a Biopharmaceutics Classification System (BCS) Class II drug, characterized by low aqueous solubility and high permeability nih.govrsc.orgseejph.comrjptonline.orgrjptonline.orginnovareacademics.inasiapharmaceutics.info. This inherent poor water solubility is the most formidable challenge in its formulation, leading to low and variable dissolution rates and, consequently, limited bioavailability nih.govseejph.comrjptonline.orgrjptonline.orginnovareacademics.inasiapharmaceutics.infoasianpubs.orgplos.org. It is practically insoluble in water and absolute ethanol, sparingly soluble in aqueous buffers, and very slightly soluble in methylene chloride, though it dissolves in dilute solutions of alkali hydroxides nih.govcaymanchem.comijnrd.org. As a weak acid with a pKa of 5.9, its aqueous solubility exhibits pH dependence, decreasing as pH increases from 1 to 3, slightly increasing at pH 4.5, and further increasing above pH 6.8 rsc.orgijnrd.org.

Another critical challenge stems from this compound's short biological half-life, typically ranging from 2 to 4 hours (or 3.4 ± 0.7 hours) nih.govrsc.orgrjptonline.org. While its bioavailability is nearly 100%, this short half-life necessitates multiple daily administrations of conventional dosage forms, which can adversely impact patient compliance and lead to fluctuating plasma drug levels rsc.orgrjptonline.orgbioresscientia.comtandfonline.comnih.govfabad.org.tr. Furthermore, the use of certain excipients, such as lower molecular weight polyethylene glycols (PEGs) in solid dispersions, can result in sticky products, complicating the manufacturing process and transformation into suitable pharmaceutical dosage forms nih.gov.

To address these multifaceted formulation challenges, various advanced pharmaceutical strategies have been developed and extensively researched.

Personalized Medicine Approaches and Pharmacogenomics of Glipizide ResponsePersonalized medicine, enabled by pharmacogenomics, aims to tailor drug therapy to an individual's unique genetic makeup, optimizing efficacy and minimizing adverse effectsnih.gov. The glycemic response to oral antidiabetic agents, including sulfonylureas like this compound, exhibits considerable inter-individual variability, which is partly attributable to genetic factorsnih.gov. Research initiatives, such as the Study to Understand the Genetics of the Acute Response to Metformin and this compound in Humans (SUGAR-MGH), have been instrumental in identifying pharmacogenetic associations with this compound responsenih.govdiabetesjournals.orgmassgeneral.orgkaiserpermanente.org.

Key research findings highlight the influence of specific genetic variants on this compound's effectiveness. For instance, the rs7903146 T allele in the transcription factor 7 like 2 (TCF7L2) gene has been shown to influence acute responses to this compound harvard.edu. Furthermore, ancestry-specific genetic variants, particularly those more common in individuals of African ancestry (e.g., rs149403252 and rs111770298), have been associated with varying responses to this compound (and metformin) nih.govmassgeneral.org. A genome-wide meta-analysis identified two independent loci near the GXYLT1 and SLCO1B1 genes linked to reductions in HbA1c with sulfonylureas. Specifically, the C allele at rs1234032, located near GXYLT1, was associated with a higher post-dose glucose trough level and thus a worse response to this compound in healthy volunteers diabetesjournals.org. Understanding these genetic influences is crucial for guiding and tailoring treatment selection for diverse patient populations in the future massgeneral.org.

Long-Term Outcomes and Cardiovascular Implications ResearchResearch into the long-term outcomes and cardiovascular implications of this compound is a critical area of study, particularly in comparison to other antidiabetic medications. Studies have compared the long-term effects of this compound with metformin on major cardiovascular events in patients with type 2 diabetes and coronary artery disease (CAD). A multicenter, randomized, double-blind clinical trial involving 304 patients demonstrated that treatment with metformin for three years substantially reduced major cardiovascular events over a median follow-up of 5.0 years compared to glipizidenih.govnih.govresearchgate.netresearchgate.net. The adjusted hazard ratio for composite cardiovascular events was 0.54 (95% CI 0.30-0.90; P = 0.026) for metformin compared with glipizidenih.govnih.govresearchgate.net.

Further nationwide studies have indicated that this compound may be associated with higher all-cause and cardiovascular mortality compared to metformin, with this compound users showing a 27% higher risk of all-cause mortality and a 53% higher risk in patients with a previous myocardial infarction consensus.app. These findings underscore the ongoing need for research into the long-term cardiovascular safety profile of this compound, especially in comparison to newer antidiabetic agents or metformin, to inform clinical guidelines and patient management strategies.

Role of this compound in Specific Patient Populations (e.g., Chronic Kidney Disease, Elderly)Research continues to delineate the role of this compound in specific patient populations, particularly those with chronic kidney disease (CKD) and the elderly, where physiological changes can significantly impact drug pharmacokinetics and pharmacodynamics.

Chronic Kidney Disease (CKD): this compound's use in patients with CKD requires careful consideration. While some studies suggest it may not always necessitate dose adjustment in mild to moderate CKD (eGFR >30 mL/min), its use in advanced kidney disease should be approached with caution due to an increased risk of hypoglycemia droracle.ainih.govdroracle.ai. This compound is often preferred over some other sulfonylureas in CKD because it does not produce active metabolites that accumulate in renal impairment droracle.ai. However, its effects can be prolonged in patients with kidney impairment, indirectly affecting kidney function through hypoglycemia droracle.ai. Comparative studies, such as those evaluating sitagliptin versus this compound in patients with type 2 diabetes and moderate-to-severe chronic renal insufficiency, have shown similar HbA1c-lowering efficacy. However, sitagliptin was associated with a lower incidence of symptomatic hypoglycemia and a decrease in body weight, whereas this compound led to weight gain droracle.aidiabetesjournals.orgeurekalert.orgnih.gov.

Elderly: In elderly patients, this compound has shown effectiveness in glycemic control. However, studies indicate a significant risk of hypoglycemia associated with second-generation sulfonylureas, including this compound, in this population nih.govdiabetesjournals.org. While appropriate studies have not definitively limited this compound's usefulness in the elderly, age-related impairments in heart, liver, or kidney function warrant caution mayoclinic.org. Close surveillance of ambulatory glucose monitoring and intensive patient education regarding hypoglycemia risks are crucial for the proper use of sulfonylureas in elderly individuals nih.govdiabetesjournals.org.

Advanced Preclinical Models for this compound ResearchAdvanced preclinical models are instrumental in uncovering novel mechanisms and potential therapeutic applications of this compound beyond its traditional antidiabetic role. High-throughput screening (HTS) using in vivo models, such as the chick embryo chorioallantoic membrane (CAM) and yolk sac membrane (YSM) models, has identified this compound's significant inhibitory effects on blood vessel formation and developmentresearchgate.netnih.govoncotarget.com.

Further research employing xenograft tumor and MMTV-PyMT transgenic mouse models has demonstrated this compound's ability to suppress tumor angiogenesis, tumor growth, and metastasis researchgate.netnih.govoncotarget.com. Notably, these anticancer effects are not attributed to its antidiabetic properties, as another sulfonylurea, glimepiride, did not exhibit similar impacts on tumor growth and metastasis researchgate.netnih.govoncotarget.com. Preclinical studies have also explored this compound's potential in combination with TRAIL to treat cancer cells, its role in suppressing vasculogenesis, and its protective effects against glycation-induced cellular damage nih.gov. Additionally, in vivo experiments have revealed anticonvulsant effects and modifications in the pharmacokinetics of other medications by this compound nih.gov. Research on novel formulations, such as this compound microemulsions, utilizes in vitro diffusion studies with mouse skin and in vivo studies in male albino rats to assess enhanced drug delivery and efficacy in managing induced diabetes wisdomlib.org.

Integration of Artificial Intelligence and Machine Learning in this compound ResearchThe integration of Artificial Intelligence (AI) and Machine Learning (ML) is rapidly transforming pharmaceutical research, including investigations into this compound. These technologies are being applied across various stages, from drug formulation to predicting patient responses and optimizing clinical trial designsgsconlinepress.commdpi.comnih.gov.

AI and ML algorithms can analyze vast datasets derived from electronic health records, clinical trials, and observational studies to identify complex patterns and predict individual responses to drugs like this compound nih.gov. This capability is crucial for advancing personalized medicine, enabling the selection of the most effective therapeutic agents for specific patients and optimizing treatment regimens nih.gov. Specific applications include the development of this compound push-pull osmotic pump controlled-release tablets using expert systems and artificial neural networks, demonstrating how AI can optimize drug formulation for improved delivery gsconlinepress.com. Furthermore, ML techniques have been employed to predict hospital readmission rates and identify risk features in diabetic patients, with analyses sometimes including the impact of medications like this compound on these rates, as visualized through tools like Partial Dependence Plots (PDP) researchgate.net. The broader potential of AI and ML in this compound research lies in its capacity to revolutionize the development of personalized biologics and to identify novel treatment targets by integrating clinical, protein, and genomic data mdpi.com.

Q. What experimental methodologies are recommended for quantifying glipizide in pharmacokinetic studies?

High-performance liquid chromatography (HPLC) with UV detection is widely used due to its specificity and sensitivity. Key parameters include:

• Column : C18 reverse-phase (e.g., 250 mm × 4.6 mm, 5 µm particle size).
• Mobile phase : Acetonitrile-phosphate buffer (pH 3.0) in a 40:60 ratio.
• Flow rate : 1.0 mL/min.
• Detection wavelength : 225 nm. Validation should follow ICH guidelines for linearity (1–50 µg/mL), precision (RSD <2%), and recovery (>95%) .

Q. How should preclinical studies be designed to evaluate this compound’s mechanism of action in glucose regulation?

• In vitro : Use pancreatic β-cell lines (e.g., INS-1) to measure insulin secretion under varying glucose concentrations (5–25 mM) with this compound (1–100 nM).
• In vivo : Employ streptozotocin-induced diabetic rodent models, administering this compound (2.5–10 mg/kg) and monitoring blood glucose via glucometers at 0, 30, 60, and 120 minutes post-dose. Include control groups (vehicle and healthy animals) and validate results with Western blotting for SUR1 receptor expression .

Q. What statistical approaches are appropriate for analyzing this compound’s efficacy in clinical trials?

Use ANOVA for comparing HbA1c reduction across treatment arms (e.g., this compound vs. placebo), followed by post-hoc Tukey tests. For time-series glucose data, mixed-effects models account for intra-patient variability. Sample size calculations should assume a 0.5% HbA1c difference with 80% power and α=0.05 .

Advanced Research Questions

Q. How can contradictory findings on this compound’s cardiovascular risks be resolved in meta-analyses?

• Data stratification : Separate studies by patient comorbidities (e.g., CVD history) and this compound dosage (≤10 mg/day vs. >10 mg/day).
• Sensitivity analysis : Exclude trials with high attrition rates (>20%) or unblinded designs.
• Meta-regression : Investigate confounding variables like concomitant metformin use. Tools like Cochrane’s ROBINS-I should assess bias .

Q. What in silico strategies are effective for predicting this compound-drug interactions at the CYP2C9 enzyme?

• Molecular docking : Use AutoDock Vina to simulate this compound binding to CYP2C9 (PDB ID: 1OG5).
• Pharmacophore modeling : Identify critical interaction sites (e.g., sulfonylurea moiety).
• Machine learning : Train random forest models on datasets like DrugBank to predict inhibition constants (Ki). Validate with in vitro microsomal assays .

Q. How do genetic polymorphisms (e.g., CYP2C9*3) impact this compound pharmacokinetics across diverse populations?

• Study design : Recruit cohorts stratified by CYP2C9 genotypes (e.g., *1/*1, *1/*3).
• PK parameters : Calculate AUC0–∞, Cmax, and t1/2 via non-compartmental analysis (WinNonlin).
• Statistical modeling : Use NONMEM for population PK analysis, incorporating covariates like BMI and renal function. Ethical considerations: Ensure informed consent addresses genetic data privacy .

Methodological Guidance

Q. What criteria define a robust literature review for identifying gaps in this compound research?

• Search strategy : Combine terms (e.g., “this compound AND pharmacokinetics NOT metformin”) across PubMed, Scopus, and Web of Science, limited to 2010–2025.
• Screening : PRISMA flowchart to document inclusion/exclusion.
• Quality assessment : Apply Newcastle-Ottawa Scale for observational studies. Highlight understudied areas (e.g., long-term neurocognitive effects) .

Q. How can researchers optimize this compound formulation stability in dissolution studies?

• Accelerated stability testing : Store tablets at 40°C/75% RH for 6 months. Monitor degradation products via LC-MS.
• Dissolution media : Use pH 1.2 (HCl), 4.5 (acetate), and 6.8 (phosphate) to simulate gastrointestinal conditions.
• Kinetic modeling : Apply Weibull equations to predict shelf-life .

Data Presentation & Reproducibility

Q. What are the best practices for reporting this compound clinical trial data to ensure reproducibility?

• Raw data : Deposit in repositories like ClinicalTrials.gov or Dryad.
• Preprocessing : Document outlier removal criteria (e.g., values beyond ±3 SD).
• Visualization : Use Forest plots for meta-analyses and heatmaps for gene expression correlations. Follow CONSORT guidelines for flow diagrams and EQUATOR Network standards .

Q. How should conflicting in vitro vs. in vivo this compound efficacy data be reconciled?

• Dose translation : Apply allometric scaling (e.g., body surface area adjustment) between cell culture (µM) and animal models (mg/kg).
• Tissue distribution : Measure this compound concentrations in pancreatic tissue via LC-MS/MS.
• Mechanistic studies : Use knockout mice (e.g., SUR1−/−) to isolate target effects .