Pharmacokinetic and Bioequivalence Studies of 2 Metformin Glibenclamide Tablets in Healthy Chinese Subjects Under Fasting and Fed Conditions.

The rational combination of oral antidiabetic agents is more likely to provide better glycemic control than monotherapy. Metformin glibenclamide tablets can be used as second-line therapy for patients with type 2 diabetes mellitus who cannot successfully control their blood glucose levels by diet and exercise plus metformin or sulfonylureas. The aim of this study was to evaluate the bioequivalence and safety of metformin hydrochloride and glibenclamide tablets (500 mg/5 mg) prepared by 2 different vendors in healthy Chinese subjects under fasting and fed conditions. This is an open-label, single-center, randomized, 2-formulation, 2-period crossover study. After screening, 40 subjects were enrolled in the fasting trial, while 40 subjects were enrolled in the fed trial. Qualified subjects were randomly assigned to receive a monotherapy dose of 500 mg/5 mg of the test or reference formulation, and after a 1-week washout period, they took the alternative formulation. Blood samples were collected from 24 blood collection sites per cycle for pharmacokinetic analysis until 36 hours after oral administration. In total, 78 subjects completed the study. Under fasting and fed conditions, the geometric mean ratios of maximum plasma concentration, area under the plasma concentration-time curve (AUC) from time 0 to time of last quantifiable drug level , and AUC from time 0 to infinity between the 2 products, as well as the corresponding 90%CIs, were all within the range of 80%-125%. It was found that exposure (AUC from time 0 to infinity) to metformin is decreased by about 25% in the fed state compared to fasting, whereas glibenclamide exposure is increased by about 30% in the fed state. No severe adverse events were observed in the study.

Spectroscopic interactions of non-insulin-dependent diabetes mellitus with levocetirizine.

Non insulin dependent diabetes mellitus (NIDDM) drugs such as glibenclamide and metformin is employed to heterogeneous disorder characterized by alteration in production of glucose due to impairment of both insulin secretion and insulin action. These patients might suffer with allergic rhinitis and in this case, there is a possibility to maintain patient on levocetirizine, an anti-allergic drug commonly used in rhinitis. The object of the present study is to detect possible interaction between glibenclamide or metformin with levocetirizine Current study was performed using UV spectroscopic technique sing simultaneous equation in pH simulated to gastric juice (pH 1), pH 4, pH 7.4 and in pH 9. All drugs followed Beer Lambert's Law. Results showed that glibenclamide and metformin can increase or decrease availability of levocetirizine and in the same way levocetirizine can alter availabilities of glibenclamide and metformin in different pH. Hence, drug interaction between glibenclamide or metformin with levocetirizne occurred. This may be due to his may be due to the charge transfer or binding capabilities of these drugs which resulted in significantly changed availability of NIDDIM as well as levocetirizine. Therefore, co-administration of these drugs should be avoided and furtherinvestigations at clinical and pre-clinical levels should be done.

Drug metabolism-related eight-gene signature can predict the prognosis of gastric adenocarcinoma.

BACKGROUND: Metabolic abnormalities in patients with gastric adenocarcinoma lead to drug resistance and poor prognosis. Therefore, this study aimed to explore biomarkers that can predict the prognostic risk of gastric adenocarcinoma by analyzing drug metabolism-related genes. METHODS: The RNA-seq and clinical information on gastric adenocarcinoma were downloaded from the UCSC and gene expression omnibus databases. Univariate and least absolute shrinkage and selection operator regression analyses were used to identify the prognostic gene signature of gastric adenocarcinoma. The relationships between gastric adenocarcinoma prognostic risk and tumor microenvironment were assessed using CIBERSORT, EPIC, QUANTISEQ, MCPCounter, xCell, and TIMER algorithms. The potential drugs that could target the gene signatures were predicted in WebGestalt, and molecular docking analysis verified their binding stabilities. RESULTS: Combined with clinical information, an eight-gene signature, including GPX3, ABCA1, NNMT, NOS3, SLCO4A1, ADH4, DHRS7, and TAP1, was identified from the drug metabolism-related gene set. Based on their expressions, risk scores were calculated, and patients were divided into high- and low-risk groups, which had significant differences in survival status and immune infiltrations. Risk group was also identified as an independent prognostic factor of gastric adenocarcinoma, and the established prognostic and nomogram models exhibited excellent capacities for predicting prognosis. Finally, miconazole and niacin were predicted as potential therapeutic drugs for gastric adenocarcinoma that bond stably with NOS3 and NNMT through hydrogen interactions. CONCLUSIONS: This study proposed a drug metabolism-related eight-gene signature as a potential biomarker to predict the gastric adenocarcinoma prognosis risks.

Hypoglycemia and Glycemic Control With Glyburide in Women With Gestational Diabetes and Genetic Variants of Cytochrome P450 2C9 and/or OATP1B3.

Glyburide is mainly metabolized by the cytochrome P450 2C9 (CYP2C9) enzyme and enters the liver via the transporter OATP1B3. The variants OATP1B3*4 (699 G>A; rs7311358) and CYP2C9*2 and *3 are known to have a significant influence on the hepatic uptake and metabolism of glyburide, with lower clearance than in the wild type. In an ancillary study of the INDAO trial, we selected 117 pregnant women with gestational diabetes treated by glyburide and assessed the role of the combined CYP2C9 and OATP1B3 genetic polymorphisms in hypoglycemia and glycemic control. Three groups were constituted: (1) the wild-type genotype group (wild-type allele genotype for both CYP2C9*1 and OATP1B3*1 (699G)), (2) the intermediate group (carriers of CYP2C9*2 allele or OATP1B3*4 (699G>A) heterozygous), and (3) the variant group (carriers of CYP2C9*3 allele and/or OATP1B3*4 (699G>A) homozygous variant). We found that the risk of hypoglycemia was significantly higher in the variant genotype at the second week of treatment: 20.0% (4/20) vs. 8.1% (3/37) in the intermediate group and 4.1% (2/49) in the wild-type genotype group (P = 0.03). The last daily dose of glyburide during pregnancy was lower for patients in the variant genotype group: 4.7 mg (SD 3.5) vs. 8.7 mg (SD 5.7) in the wild-type group and 5.7 mg (SD 3.7) in the intermediate group (P < 0.01). In conclusion, the no-function variants CYP2C9*3 and OATP1B3*4 are associated with a higher risk of hypoglycemia and a lower dose of glyburide in women with gestational diabetes treated with glyburide, which is consistent with the pharmacokinetic roles of both CYP2C9 and OATP1B3.

Bioequivalence and pharmacokinetic comparison of two fixed dose combination of Metformin/ Glibenclamide formulations in healthy subjects under fed condition.

AIM: This study is conducted to compare the pharmacokinetic profiles of two fixed dose combination of metformin/glibenclamide tablets (500mg/5 mg per tablet). MATERIALS AND METHODS: This is a single-center, single-dose, open-label, randomized, 2-treatment, 2-sequence and 2- period crossover study with a washout period of 7 days. All 28 adult male subjects were required to fast for at least 10 hours prior to drug administration and they were given access to water ad libitum during this period. Thirty minutes prior to dosing, all subjects were served with a standardized high-fat and high-calorie breakfast with a total calorie of 1000 kcal which was in accordance to the EMA Guideline on the Investigation of Bioequivalence. Subsequently, subjects were administered either the test or reference preparation with 240mL of plain water in the first trial period. During the second trial period, they received the alternate preparation. Plasma levels of glibenclamide and metformin were analysed separately using two different high performance liquid chromatography methods. RESULTS: The 90% confidence interval (CI) for the ratio of the AUC0-t, AUC0-∞, and Cmax of the test preparation over those of the reference preparation were 0.9693-1.0739, 0.9598- 1.0561 and 0.9220 - 1.0642 respectively. Throughout the study period, no serious drug reaction was observed. However, a total of 26 adverse events (AE)/side effects were reported, including 24 that were definitely related to the study drugs, namely giddiness (n=17), while diarrheoa (n=3), headache (n=2) and excessive hunger (n=2) were less commonly reported by the subjects. CONCLUSION: It can be concluded that the test preparation is bioequivalent to the reference preparation.

Central KATP Channels Modulate Glucose Effectiveness in Humans and Rodents.

Hyperglycemia is a potent regulator of endogenous glucose production (EGP). Loss of this "glucose effectiveness" is a major contributor to elevated plasma glucose concentrations in type 2 diabetes (T2D). KATP channels in the central nervous system have been shown to regulate EGP in humans and rodents. We examined the contribution of central KATP channels to glucose effectiveness. Under fixed hormonal conditions (studies using a pancreatic clamp), hyperglycemia suppressed EGP by ∼50% in both humans without diabetes and normal Sprague-Dawley rats. By contrast, antagonism of KATP channels with glyburide significantly reduced the EGP-lowering effect of hyperglycemia in both humans and rats. Furthermore, the effects of glyburide on EGP and gluconeogenic enzymes were abolished in rats by intracerebroventricular administration of the KATP channel agonist diazoxide. These findings indicate that about half of the suppression of EGP by hyperglycemia is mediated by central KATP channels. These central mechanisms may offer a novel therapeutic target for improving glycemic control in subjects with T2D.

Pharmacodynamic interaction of cumin seeds (Cuminum cyminum L.) with glyburide in diabetes.

Background and objective The plethora of anti-diabetic agents available today has many side effects, especially on chronic usage. Hence, alternative approaches utilizing natural and synthetic agents are sought after. Cumin has been shown to be beneficial in treating diabetes. This study evaluates the anti-diabetic effect of cumin and glyburide in the streptozotocin induced diabetes model in rats, and investigates their pharmacodynamic interactions and its implication in diabetes. Methodology The phytoconstituents present in the ethanolic cumin seed extract were determined using appropriate analytical methods. After acute toxicity studies (OECD 2001), the anti-diabetic effect of the extract was evaluated in wistar rats. The rats were divided into five groups - Groups I and II served as the normal and diabetic control. Group III was the standard control (glyburide 5 mg/kg), while groups IV and V received the extract (600 mg/kg) and a combination of the extract (600 mg/kg) and glyburide (2.5 mg/kg; half dose). Biochemical parameters viz. plasma glucose and glycosylated haemoglobin, were measured periodically during the 28 day treatment. On the 28th day, oral glucose tolerance test, lipid profile, renal profile and histopathological evaluation were performed after completion of the study. To investigate the nature of herb-drug interaction, HPLC analysis for estimation of glyburide concentration in the blood was conducted. Results Acute toxicity studies showed the extract to be safe till a dose of 2 g/kg. The extract alone, and in combination with glyburide (half-dose), significantly lowered elevated glucose (by more than 45% from baseline; without producing hypoglycemia), and other lipid and renal parameters. The effects produced by 2.5 mg/kg glyburide, and 5 mg/kg glyburide (without extract) were similar. Histopathological analysis also showed that the extract was able to reverse the degeneration brought about by streptozotocin which was especially notable on the pancreatic and renal tissue. HPLC analysis revealed differing pharmacokinetics of glyburide in the groups treated with 5 mg/kg dose, and 2.5 mg/kg + 600 mg/kg extract. Conclusion The results obtained in this study suggest that Cuminum cyminum L. is a promising anti-diabetic agent, and exhibits pharmacodynamic interaction with glyburide to mitigate symptoms of diabetes mellitus.

The influence of drug solubility and sampling frequency on metformin and glibenclamide release from double-layered particles: experimental analysis and mathematical modelling.

Co-axial electrohydrodynamic atomization was used to prepare core/shell polymethylsilsesquioxane particles for co-delivery of metformin and glibenclamide in a sustained release manner. The drug-loaded microparticles were mostly spherical and uniformly distributed in size, with average diameters between 3 and 5 µm across various batches. FTIR was used to confirm the presence of drugs within the particles while X-ray diffraction studies revealed drugs encapsulated existed predominantly in the amorphous state. Intended as systems that potentially can act as depot formulations for long-term release of antidiabetics, a detailed analysis of drug release from these particles was necessary. Drugs of different solubilities were selected in order to study the effects of drug solubility from a core/shell particle system. Further analyses to determine how conditions such as release into a limited volume of media, sampling rate and partitioning of drug between the core and shell layers influenced drug release were conducted by comparing experimental and mathematically modelled outcomes. It was found that while the solubility of drug may affect release from such systems, rate of removal of drug (sampling frequency) which upsets local equilibrium at the particle/solution interface prompting a rapid release to redress the equilibrium influenced release more.

Engineering of solidified glyburide nanocrystals for tablet formulation via loading of carriers: downstream processing, characterization, and bioavailability.

INTRODUCTION: Presenting poorly water-soluble drugs as nanoparticles has shown to be an effective technique in enhancing drug dissolution rate, intrinsic solubility, and thus oral bioavailability. Nevertheless, working with nanoparticles introduces many challenges, one of which is their physical instability. Formulating nanoparticles into a solid dosage form may overcome such challenges and thus unlock the potential benefits of nanosizing. METHODS: The current work investigates the possibility of developing a novel solid dosage form, with enhanced dissolution rate, whereby nanocrystals (~400 nm) of the class II Biopharmaceutical Classification System drug, glyburide (GBD) were fabricated through combined precipitation and homogenization procedures. Using a novel, but scalable, spraying technique, GBD nanocrystals were loaded onto commonly used tablet fillers, water-soluble lactose monohydrate (LAC), and water insoluble microcrystalline cellulose (MCC). Conventional tableting processes were then used to convert the powders generated into a tablet dosage form. RESULTS: Studies of redispersibility showed considerable preservation of size characteristics of GBD nanocrystals during downstream processing with redispersibility indices of 105 and 118 for GBD-LAC and GBD-MCC, respectively. Characterization by differential scanning calorimetry, powder X-ray diffraction, and scanning electron microscopy showed that the powders generated powders contained nanosized crystals of GBD which adhered to carrier surfaces. Powder flowability was characterized using Hausner ratio (HR) and Carr's index (CI). GBD-LAC-loaded particles exhibited poor flowability with CI and HR of 37.5% and 1.60, respectively, whilst GBD-MCC particles showed a slightly improved flowability with CI and HR of 26.47% and 1.36, respectively. The novel tablet dosage form met US Pharmacopeia specifications, including drug content, hardness, and friability. CONCLUSION: Higher dissolution rates were observed from the nanocrystal-based tablets compared to the microsized and commercial drug formulations. Moreover, the novel nanocrystal tablet dosage forms showed enhanced in vivo performance with area under the plasma concentration- time curve in the first 24 hours values 1.97 and 2.24 times greater than that of marketed tablets.

Strategies to improve the prediction accuracy of hepatic intrinsic clearance of three antidiabetic drugs: Application of the extended clearance concept and consideration of the effect of albumin on CYP2C metabolism and OATP1B-mediated hepatic uptake.

The antidiabetic drugs glibenclamide, repaglinide, and nateglinide are well-known substrates for hepatic uptake transporters of the organic anion transporting polypeptide (OATP) family and metabolizing enzymes of the cytochrome P450 (CYP) 2C subfamily. The systemic exposure of these drugs varies substantially among individuals, impacted by genetic polymorphisms of transporters and metabolizing enzymes as well as drug-drug interactions. The use of the conventional in vitro-in vivo extrapolation (IVIVE) method was found to underestimate their hepatic intrinsic clearance (CLint,all); the clinically observed CLint,all values were ≥10-fold higher than the predicted values from in vitro data. In order to improve the accuracy in predicting CLint,all of these drugs, the following modifications were implemented; i) the extended clearance concept was applied during IVIVE processes, ii) albumin was added to metabolic assays using human liver microsomes (to minimize the impact of intrinsic inhibitors on kinetic parameters for CYP2C-mediated metabolism) and to hepatic uptake assays (to accommodate the enhanced hepatic uptake observed with albumin-bound drugs), and iii) differing rates of efflux and influx via diffusion were used. The IVIVE method with these modifications yielded the predicted CLint,all values from in vitro data in closer agreement with the CLint,all values observed in vivo; the fold differences between the predicted and observed CLint,all values reduced from 13-15 to 5.9-6.7. Our current approach offers an improvement in the prediction of CLint,all and further investigations are warranted to enhance the prediction accuracy of IVIVE.

Glibenclamide Mini-tablets with an Enhanced Pharmacokinetic and Pharmacodynamic Performance.

In an attempt to decrease the dose, anticipated side effects, and the cost of production of glibenclamide, GLC, a potent oral hypoglycemic drug, the enhancement of the dissolution and hence the oral bioavailability were investigated. Adsorption and co-adsorption techniques using carriers having a very large surface area and surface active agents were utilized to enhance the drug dissolution. Moreover, the Langmuir adsorption isotherms were constructed to identify the type and mechanism of adsorption. The optimized formulation showing the highest in vitro release was compressed into mini-tablet to facilitate drug administration to elderly patients and those having swallowing difficulties. The produced mini-tablets were tested for their mechanical strength and in vitro release pattern. In addition, the pharmacodynamic and pharmacokinetic studies in New Zealand rabbits were performed using the optimized mini-tablet formulation. Mini-tablets containing GLC co-adsorbate with Pluronic F-68 and Laponite RD showed 100 ± 1.88% of GLC released after 20 min. Pharmacodynamic studies in rabbits revealed significantly higher (p ≤ 0.05) hypoglycemic effect with the optimized mini-tablets at a lower GLC dose compared to mini-tablets containing the commercial GLC dose. Moreover, pharmacokinetic analysis showed significantly higher (p ≤ 0.05) AUC, Cmax, and shorter Tmax. The optimized mini-tablet formulation showed 1.5-fold enhancement of the oral bioavailability compared to mini-tablets containing untreated GLC. It could be concluded that the co-adsorption technique successfully enhanced the oral bioavailability of GLC. Furthermore, the produced mini-tablets have a higher oral bioavailability with a lower GLC dose, which could offer economic benefit for industry as well as acceptability for patients.

Permeability of glibenclamide through a PAMPA membrane: The effect of co-amorphization.

Co-amorphous systems are an attractive alternative for amorphous solid polymer dispersions in the formulation of poorly soluble drugs. Several studies have revealed that co-amorphous formulations can enhance the dissolution properties of poorly-soluble drugs and stabilize them in the amorphous form. However, the interplay between the drug dissolution rate, drug supersaturation and different co-formers on membrane permeability of the drug for co-amorphous formulations remains unexplored. By using side-by-side chambers, separated by a PAMPA (parallel artificial membrane permeability assay) membrane, we were able to simultaneously test dissolution and passive membrane permeability of the co-amorphous combinations (1:1 molar ratio) of a poorly soluble drug glibenclamide (GBC) in combination with two amino acids, either serine (SER) or arginine (ARG). In addition, a known passive permeability enhancer sodium lauryl sulfate (SLS) was included in the co-amorphous mixtures at two concentration levels. The mixtures were also characterized with respect to their solid-state properties and physical stability. It was found that GBC mixtures with ARG and SLS had superior dissolution and physical stability properties which was attributable to the strong intermolecular interactions formed between GBC and ARG. These formulations also had optimal permeability properties due to their high concentration gradient promoting permeation and possible permeation enhancing effect of the co-formers ARG and SLS. Thus, simultaneous testing of dissolution and permeation through a PAMPA membrane may represent a simple and inexpensive tool for screening the most promising amorphous formulations in further studies.

Binding of sulphonylureas to plasma proteins - A KATP channel perspective.

Sulphonylurea drugs stimulate insulin secretion from pancreatic ß-cells primarily by inhibiting ATP sensitive potassium (KATP) channels in the ß-cell membrane. The effective sulphonylurea concentration at its site of action is significantly attenuated by binding to serum albumin, which makes it difficult to compare in vitro and in vivo data. We therefore measured the ability of gliclazide and glibenclamide to inhibit KATP channels and stimulate insulin secretion in the presence of serum albumin. We used this data, together with estimates of free drug concentrations from binding studies, to predict the extent of sulphonylurea inhibition of KATP channels at therapeutic concentrations in vivo. KATP currents from mouse pancreatic ß-cells and Xenopus oocytes were measured using the patch-clamp technique. Gliclazide and glibenclamide binding to human plasma were determined in spiked plasma samples using an ultrafiltration-mass spectrometry approach. Bovine serum albumin (60g/l) produced a mild, non-significant reduction of gliclazide block of KATP currents in pancreatic ß-cells and Xenopus oocytes. In contrast, glibenclamide inhibition of recombinant KATP channels was dramatically suppressed by albumin (predicted free drug concentration <0.1%). Insulin secretion was also reduced. Free concentrations of gliclazide and glibenclamide in the presence of human plasma measured in binding experiments were 15% and 0.05%, respectively. Our data suggest the free concentration of glibenclamide in plasma is too low to account for the drug's therapeutic effect. In contrast, the free gliclazide concentration in plasma is high enough to close KATP channels and stimulate insulin secretion.

Effect of Tinospora cordifolia aqua-alcoholic extract on pharmacokinetic of Glibenclamide in rat: An herb-drug interaction study.

Tinospora cordifolia (TC) has been used as a complimentary/alternative medicine against diabetes. Considering its potential to modulate metabolic enzymes, Tinospora cordifolia extract (TCE) may influence the metabolism of the antidiabeic drug Glibenclamide following co-administration. Accordingly, this work was undertaken to evaluate impact of TCE on fate of Glibenclamide. Activity of clinically important Cytochrome P450 isoenzymes were inhibited in the order of CYP2C9 > CYP2D6 > CYP2C19 > CYP1A2 > CYP3A4. Formations of metabolites were inhibited with increasing concentration of TCE in both rat and human liver microsomes. TCE was co- administered in three different groups (0, 100 and 400 mg/kg) with Glibenclamide at 1 mg/kg dose to observe the alteration in pharmacokinetic parameters of Glibenclamide. The rats were pretreated with 0 (vehicle), 100 and 400 mg/kg dose of TCE b.i.d for 14 days and on the 14th day all three groups were administered with 1 mg/kg Glibenclamide. Pharmacokinetic parameters were analyzed based on plasma concentrations of Glibenclamide from all the groups by LC-HRMS methods using Glipizide as an internal standard. At 400 mg/kg dose, a marked increase in the bio availability of Glibenclamide was observed with a significant delay of Tmax and suppression of clearance.

Comprehensive PBPK Model of Rifampicin for Quantitative Prediction of Complex Drug-Drug Interactions: CYP3A/2C9 Induction and OATP Inhibition Effects.

This study aimed to construct a physiologically based pharmacokinetic (PBPK) model of rifampicin that can accurately and quantitatively predict complex drug-drug interactions (DDIs) involving its saturable hepatic uptake and auto-induction. Using in silico and in vitro parameters, and reported clinical pharmacokinetic data, rifampicin PBPK model was built and relevant parameters for saturable hepatic uptake and UDP-glucuronosyltransferase (UGT) auto-induction were optimized by fitting. The parameters for cytochrome P450 (CYP) 3A and CYP2C9 induction by rifampicin were similarly optimized using clinical DDI data with midazolam and tolbutamide as probe substrates, respectively. For validation, our current PBPK model was applied to simulate complex DDIs with glibenclamide (a substrate of CYP3A/2C9 and hepatic organic anion transporting polypeptides (OATPs)). Simulated results were in quite good accordance with the observed data. Altogether, our constructed PBPK model of rifampicin demonstrates the robustness and utility in quantitatively predicting CYP3A/2C9 induction-mediated and/or OATP inhibition-mediated DDIs with victim drugs.

The care of pregestational and gestational diabetes and drug metabolism considerations.

INTRODUCTION: Normal pregnancy development involves gradual decline in insulin sensitivity, which sometimes requires pharmacotherapy. Insulin is the drug of choice for gestational and pregestational diabetes. Metabolism of traditional insulins results in inadequate onset and duration of action and marked peak activity. These properties increase risk of excessive glucose excursions, which are especially undesirable during pregnancy. Insulin analogs have been emerging as a safer and more effective treatment of diabetes during pregnancy. Areas covered: This manuscript reviews currently used antihyperglycemic agents: fast and long-acting insulins, metformin and glyburide. Trials demonstrating their efficacy and safety during pregnancy are described. Certain drug metabolism considerations (e.g. affinity to IGF-1) are emphasized. Expert opinion: The theories that insulin analogs bind to immunoglobulin and cross placenta have been disproved. Lispro, aspart, glargine and detemir do not transfer across the placenta and do not result in adverse maternal and neonatal outcomes. In addition, favorable pharmacokinetic profiles (rapid onset and 24-hour near peakless activity) substantially reduce blood glucose variability including hypoglycemia. We believe that insulin analogs should be given strong consideration for the treatment of diabetes during pregnancy. Metformin has also proven to be safe and may be considered as an initial single agent for milder gestational diabetes.

Management of sulfonylurea-treated monogenic diabetes in pregnancy: implications of placental glibenclamide transfer.

The optimum treatment for HNF1A/HNF4A maturity-onset diabetes of the young and ATP-sensitive potassium (KATP ) channel neonatal diabetes, outside pregnancy, is sulfonylureas, but there is little evidence regarding the most appropriate treatment during pregnancy. Glibenclamide has been widely used in the treatment of gestational diabetes, but recent data have established that glibenclamide crosses the placenta and increases risk of macrosomia and neonatal hypoglycaemia. This raises questions about its use in pregnancy. We review the available evidence and make recommendations for the management of monogenic diabetes in pregnancy. Due to the risk of stimulating increased insulin secretion in utero, we recommend that in women with HNF1A/ HNF4A maturity-onset diabetes of the young, those with good glycaemic control who are on a sulfonylurea per conception either transfer to insulin before conception (at the risk of a short-term deterioration of glycaemic control) or continue with sulfonylurea (glibenclamide) treatment in the first trimester and transfer to insulin in the second trimester. Early delivery is needed if the fetus inherits an HNF4A mutation from either parent because increased insulin secretion results in ~800-g weight gain in utero, and prolonged severe neonatal hypoglycaemia can occur post-delivery. If the fetus inherits a KATP neonatal diabetes mutation from their mother they have greatly reduced insulin secretion in utero that reduces fetal growth by ~900 g. Treating the mother with glibenclamide in the third trimester treats the affected fetus in utero, normalising fetal growth, but is not desirable, especially in the high doses used in this condition, if the fetus is unaffected. Prospective studies of pregnancy in monogenic diabetes are needed.

Transporter-Mediated Disposition, Clinical Pharmacokinetics and Cholestatic Potential of Glyburide and Its Primary Active Metabolites.

Glyburide is widely used for the treatment of type 2 diabetes. We studied the mechanisms involved in the disposition of glyburide and its pharmacologically active hydroxy metabolites M1 and M2b and evaluated their clinical pharmacokinetics and the potential role in glyburide-induced cholestasis employing physiologically based pharmacokinetic (PBPK) modeling. Transport studies of parent and metabolites in human hepatocytes and transfected cell systems imply hepatic uptake mediated by organic anion-transporting polypeptides. Metabolites are also subjected to basolateral and biliary efflux by P-glycoprotein, breast cancer resistance protein, and multidrug resistance-associated proteins, and are substrates to renal organic anion transporter 3. A PBPK model in combination with a Bayesian approach was developed considering the identified disposition mechanisms. The model reasonably described plasma concentration time profiles and urinary recoveries of glyburide and the metabolites, implying the role of multiple transport processes in their pharmacokinetics. Predicted free liver concentrations of the parent (∼30-fold) and metabolites (∼4-fold) were higher than their free plasma concentrations. Finally, all three compounds showed bile salt export pump inhibition in vitro; however, significant in vivo inhibition was not apparent for any compound on the basis of a predicted unbound liver exposure-response effect model using measured in vitro IC50 values. In conclusion, this study demonstrates the important role of multiple drug transporters in the disposition of glyburide and its active metabolites, suggesting that variability in the function of these processes may lead to pharmacokinetic variability in the parent and the metabolites, potentially translating to pharmacodynamic variability.

The role of particle size of glyburide crystals in improving its oral absorption.

Currently, nanosizing is becoming increasingly prevalent as an efficient way for the improvement of oral drug absorption. This study mainly focuses on two points, namely the crystal properties, and the in vitro and in vivo characterizations of drug crystals during the nanosizing process. We used glyburide, an oral type 2 diabetes (T2D) medication, as our model drug. We sought to reduce the crystalline size of this drug and evaluate its absorption properties by comparing it with the original coarse drug because of previous reports about its gastrointestinal absorption insufficiency. Glyburide crystals, ranging from 237.6 to 4473 nm were prepared successfully by jet milling and media milling. The particle sizes and the crystal morphology were analyzed by characterization of the solid states, equilibrium solubility, and dissolution behavior. Additionally, pharmacokinetic study was performed in SD rats. The solid state results indicated a loss in crystallinity, amide-imidic acid interconversion, and partial amorphization during nanosizing. Further, in in vitro tests, nanocrystal formulations remarkably increased the solubility and dissolution of the drug (compared to microcrystals). In the in vivo test, reducing the particle size from 601.3 to 312.5 nm showed no improvement on the C max and AUC (0-36 h) values, while a profound slowing of the drug elimination occurred with reduction of particle size. Further reduction from 312.5 to 237.6 nm lead to a significant increase (p < 0.001) of the AUC (0-36 h) from 6857.8 ± 369.3 ng mL-1 h to 12,928.3 ± 1591.4 ng mL-1 h, respectively, in rats. Our present study confirmed that nanosizing has a tremendous impact on promoting the oral absorption of glyburide.