Pulmonary Microcirculation in Experimental Model of Pulmonary Thromboembolism after Pretreatment with Chloroquine.

Changes of pulmonary microcirculation in response to pulmonary artery embolization after pretreatment with chloroquine were studied on the model of isolated perfused rabbit lungs. The increase in the pulmonary vascular resistance and pre- and postcapillary resistance was less pronounced than after pulmonary thromboembolism after pretreatment with mibefradil (T-type Ca2+ channels blocker) or nifedipine (L-type Ca2+ channels blocker). The shifts of capillary filtration coefficient correlated with changes in the precapillary resistance. When modeling pulmonary thromboembolism after pretreatment with chloroquine combined with glibenclamide (KATP channels blocker), the studied hemodynamics parameters increased to the same extent as after pretreatment with nifedipine. The results indicate that chloroquine exhibits the properties of an L- and T-type Ca2+ channels blocker and an activator of KATP channels.

The Rat Continuous Intestine Model Predicts the Impact of Particle Size and Transporters on the Oral Absorption of Glyburide.

Oral drug absorption is known to be impacted by the physicochemical properties of drugs, properties of oral formulations, and physiological characteristics of the intestine. The goal of the present study was to develop a mathematical model to predict the impact of particle size, feeding time, and intestinal transporter activity on oral absorption. A previously published rat continuous intestine absorption model was extended for solid drug absorption. The impact of active pharmaceutical ingredient particle size was evaluated with glyburide (GLY) as a model drug. Two particle size suspensions of glyburide were prepared with average particle sizes of 42.7 and 4.1 µm. Each suspension was dosed as a single oral gavage to male Sprague Dawley rats, and concentration-time (C-t) profiles of glyburide were measured with liquid chromatography coupled with tandem mass spectrometry. A continuous rat intestine absorption model was extended to include drug dissolution and was used to predict the absorption kinetics of GLY depending on particle size. Additional literature datasets of rat GLY formulations with particle sizes ranging from 0.25 to 4.0 µm were used for model predictions. The model predicted reasonably well the absorption profiles of GLY based on varying particle size and varying feeding time. The model predicted inhibition of intestinal uptake or efflux transporters depending on the datasets. The three datasets used formulations with different excipients, which may impact the transporter activity. Model simulations indicated that the model provides a facile framework to predict the impact of transporter inhibition on drug C-t profiles. Model simulations can also be conducted to evaluate the impact of an altered intestinal lumen environment. In conclusion, the rat continuous intestine absorption model may provide a useful tool to predict the impact of varying drug formulations on rat oral absorption profiles.

Correlation of Solubility Thermodynamics of Glibenclamide with Recrystallization and In Vitro Release Profile.

The solubility of glibenclamide was evaluated in DMSO, NMP, 1,4-dioxane, PEG 400, Transcutol® HP, water, and aqueous mixtures (T = 293.15~323.15 K). It was then recrystallized to solvate and compressed into tablets, of which 30-day stability and dissolution was studied. It had a higher solubility in 1,4-dioxane, DMSO, NMP (Xexp = 2.30 × 103, 3.08 × 104, 2.90 × 104) at 323.15 K, its mixture (Xexp = 1.93 × 103, 1.89 × 104, 1.58 × 104) at 298.15 K, and 1,4-dioxane (w) + water (1-w) mixture ratio of w = 0.8 (Xexp = 3.74 × 103) at 323.15 K. Modified Apelblat (RMSD ≤ 0.519) and CNIBS/R-K model (RMSD ≤ 0.358) suggested good comparability with the experimental solubility. The minimum value of ΔG° vs ΔH° at 0.70 < x2 < 0.80 suggested higher solubility at that molar concentration. Based on the solubility, it was recrystallized into the solvate, which was granulated and compressed into tablets. Among the studied solvates, the tablets of glibenclamide dioxane solvate had a higher initial (95.51%) and 30-day (93.74%) dissolution compared to glibenclamide reference (28.93%). There was no stability issue even after granulation, drying, or at pH 7.4. Thus, glibenclamide dioxane solvate could be an alternative form to improve the molecule's properties.

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.

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.

Synthesis of a novel glibenclamide-pioglitazone hybrid compound and its effects on glucose homeostasis in normal and insulin-resistant rats.

A new library of hybrid compounds that combine the functional parts of glibenclamide and pioglitazone was designed and developed. Compounds were screened for their antihyperglycemic effects on the glucose tolerance curve. This approach provided a single molecule that optimizes the pharmacological activities of two drugs used for the treatment of diabetes mellitus type 2 (DM2) and that have distinct biological activities, potentially minimizing the adverse effects of the original drugs. From a total of 15 compounds, 7 were evaluated in vivo; the compound 2; 4- [2- (2-phenyl-4-oxo-1,3-thiazolidin-3-yl) ethyl] benzene-1-sulfonamide (PTEBS) was selected to study its mechanism of action on glucose and lipid homeostasis in acute and chronic animal models related to DM2. PTEBS reduced glycemia and increased serum insulin in hyperglycemic rats, and elevated in vitro insulin production from isolated pancreatic islets. This compound increased the glycogen content in hepatic and muscular tissue. Moreover, PTEBS stimulated the uptake of glucose in soleus muscle through a signaling pathway similar to that of insulin, stimulating translocation and protein synthesis of glucose transporter 4 (GLUT4). PTEBS was effective in increasing insulin sensitivity in resistance rats by stimulating increased muscle glucose uptake, among other mechanisms. In addition, this compound reduced total triglycerides in a tolerance test to lipids and reduced advanced glycation end products (AGES), without altering lactate dehydrogenase (LDH) activity. Thus, we suggest that PTEBS may have similar effects to the respective prototypes, which may improve the therapeutic efficacy of these molecules and decrease adverse effects in the long-term.

Surfactant-Free Glibenclamide Nanoparticles: Formulation, Characterization and Evaluation of Interactions with Biological Barriers.

PURPOSE: The aim of this work was to formulate and characterize surfactant-free glibenclamide nanoparticles using Eudragit RLPO and polyethylene glycol as sole stabilizer. METHODS: Glibenclamide nanoparticles were obtained by nanoprecipitation and evaluated in terms of drug content, encapsulation efficiency, apparent saturation solubility, drug release profile, solid state and storage stability. The influence of different stirring speed on the particle size, size distribution and zeta potential of the nanoparticles was investigated. The nanoparticle biocompatibility and permeability were analyzed in vitro on Caco-2 cell line (clone HTB-37) and its interaction with mucin was also investigated. RESULTS: It was found that increasing the molecular weight of polyethylene glycol from 400 to 6000 decreased drug encapsulation, whereas the aqueous solubility and dissolution rate of the drug increased. Particle size of the nanoformulations, with and without polyethylene glycol, were between 140 and 460 nm. Stability studies confirmed that glibenclamide nanoparticles were stable, in terms of particle size, after 120 days at 4°C. In vitro studies indicated minimal interactions of glibenclamide nanoparticles and mucin glycoproteins suggesting favorable properties to address the intestinal mucus barrier. Cell viability studies confirmed the safety profile of these nanoparticles and showed an increased permeation through epithelial cells. CONCLUSION: Taking into consideration these findings, polyethylene glycol is a useful polymer for stabilizing these surfactant-free glibenclamide nanoparticles and represent a promising alternative to improve the treatment of non-insulin dependent diabetes.

Glyburide inhibits non-enzymatic glycation of HSA: An approach for the management of AGEs associated diabetic complications.

Advanced glycation endproducts (AGEs) are the final product of glycation, highly reactive in nature and contribute directly or indirectly to numerous complications related to diabetes. In this study, the antiglycation activity of glyburide was investigated using HSA as model protein, both against glucose and methylglyoxal mediated glycation. The possible mechanism of action was also deciphered using biophysical and computational tools. Approximately 70% inhibition of both early and advanced glycation end products were recorded in the presence of glyburide. Free lysine modification was reduced by glyburide treatment and improvement in biochemical markers such as free thiol groups and carbonyl content was observed. Interaction studies revealed that glyburide showed moderate to strong binding affinity towards HSA with binding constant in the order of 106 M-1. The interaction of glyburide with HSA was entropically favourable and spontaneous in nature. Molecular dynamics simulation deciphered that glyburide-HSA complex was quite stable where RMSD, RMSF, Rg, SASA, and secondary structure of HSA remained approximately same over the entire simulation period. The average binding energy of the MD simulation for glyburide-HSA complex was found to be -15.386 kJ mol-1. The findings demonstrate the antiglycation potential of glyburide and its possible mechanism of action.

In Vitro Enzymatic Conversion of Glibenclamide Using Squalene Hopene Cyclase from Pseudomonas mendocina Expressed in E. coli BL21 (DE3).

Squalene hopene cyclases catalyse the conversion of a linear substrate squalene to a cyclic product with high stereo-selectivity.The enzyme squalene hopene cyclase from Pseudomonas mendocina expressed in E. coli BL21 (DE3) was evaluated for its synthetic drug transforming ability. Nine synthetic drugs were selected as substrates for biotransformation reactions by the enzyme. The homology modelling of the protein and docking of the selected ligands were performed using GOLD suite docking software. The drug which showed maximum binding with the active-site residues of the enzyme was selected for biotransformation studies. On transformation with the enzyme, Glibenclamide, the selected antidiabetic drug alone showed significant changes in the FT/IR spectra; hence, it was selected for LCMS analysis to confirm the transformations. From the chromatogram and MS spectra, the mono-oxygenation of the product due to the enzymatic activity was confirmed. The drug transforming ability of the purified SHC could be used as an ideal tool for the generation of new and active substrate derivatives.

Ligand and structure-based virtual screening applied to the SARS-CoV-2 main protease: an in silico repurposing study.

Aim: The identification of drugs for the coronavirus disease-19 pandemic remains urgent. In this manner, drug repurposing is a suitable strategy, saving resources and time normally spent during regular drug discovery frameworks. Essential for viral replication, the main protease has been explored as a promising target for the drug discovery process. Materials & methods: Our virtual screening pipeline relies on the known 3D properties of noncovalent ligands and features of crystalized complexes, applying consensus analyses in each step. Results: Two oral (bedaquiline and glibenclamide) and one buccal drug (miconazole) presented 3D similarity to known ligands, reasonable predicted binding modes and micromolar predicted binding affinity values. Conclusion: We identified three approved drugs as promising inhibitors of the main viral protease and suggested design insights for future studies for development of novel selective inhibitors.

Computational Drug Repositioning for Chagas Disease Using Protein-Ligand Interaction Profiling.

Chagas disease, caused by Trypanosoma cruzi (T. cruzi), affects nearly eight million people worldwide. There are currently only limited treatment options, which cause several side effects and have drug resistance. Thus, there is a great need for a novel, improved Chagas treatment. Bifunctional enzyme dihydrofolate reductase-thymidylate synthase (DHFR-TS) has emerged as a promising pharmacological target. Moreover, some human dihydrofolate reductase (HsDHFR) inhibitors such as trimetrexate also inhibit T. cruzi DHFR-TS (TcDHFR-TS). These compounds serve as a starting point and a reference in a screening campaign to search for new TcDHFR-TS inhibitors. In this paper, a novel virtual screening approach was developed that combines classical docking with protein-ligand interaction profiling to identify drug repositioning opportunities against T. cruzi infection. In this approach, some food and drug administration (FDA)-approved drugs that were predicted to bind with high affinity to TcDHFR-TS and whose predicted molecular interactions are conserved among known inhibitors were selected. Overall, ten putative TcDHFR-TS inhibitors were identified. These exhibited a similar interaction profile and a higher computed binding affinity, compared to trimetrexate. Nilotinib, glipizide, glyburide and gliquidone were tested on T. cruzi epimastigotes and showed growth inhibitory activity in the micromolar range. Therefore, these compounds could lead to the development of new treatment options for Chagas disease.

Development and characterization of metformin hydrochloride- and glyburide-containing orally disintegrating tablets.

Diabetes is characterized by chronic hyperglycemia. Although metformin hydrochloride (MHCl)- and glyburide (GLB)-containing conventional tablets are available in the market and used to treat diabetes, orally disintegrating tablets (ODTs) containing the combination of these drugs are not commercially available. Therefore, the aim of this study was to prepare ODTs containing MHCl and GLB by direct-compression (DC-ODTs) and freeze-drying (FD-ODTs) methods. Physical properties of the powder mixture of DC-ODT formulation were determined (Angle of repose: 37.18 ± 1.27°; compressibility index: 20.31 ± 1.06%; Hausner ratio: 1.25 ± 0.03). Its moisture content was 0.3 ± 0.09%. The hardness values and the disintegration times for DC-ODTs and FD-ODTs were 221.60 ± 40.82 and 66.54 ± 2.68 N, and 80 and 30 s, respectively. Friability values were 0.24% for DC-ODTs and 0.38% for FD-ODTs. In uniformity-of-mass for single-dose-preparations test, the average weight was 684.38 ± 1.97 mg for DC-ODTs and 342.93 ± 2.4 mg for FD-ODTs, with less than 5% deviation for all 20 tablets. Water-absorption ratio for DC-ODTs was 1.30 ± 0.05. More than 90% of MHCl and GLB were dissolved within 5 min in both DC-ODTs and FD-ODTs. Although Caco-2 permeability of MHCl was influenced by the ODTs, GLB permeability was not. These results indicated that MHCl- and GLB-containing ODTs may be used as promising formulations for the treatment of diabetes.

One-pot synthesis of the organomodified layered double hydroxides - glibenclamide biocompatible nanoparticles.

In this work, synthesis of sodium dodecyl sulfate (SDS) organomodified LDH Zn2Al carrying glibenclamide (GLIB) was performed in one step and in one-pot to obtain nanoparticles (NP). XRD data showed GLIB adsolubilization (d = 14.03 Å) and NP coating with Eudragit L100®. In addition, thermal and XRD data showed exfoliated/intercalated nanocomposite for NP S5 (LDH associated with SDS and Eudragit L100®). LDH organophilization and GLIB intercalation reduced surface area (SBET 23.58 m2/g) and NP size (469 nm). In addition, the change in zeta potential (-35.5 ζ) relative to pristine LDH (SBET 41.34 m2/g, 688.8 nm and +14 ζ) indicated that LDH functionalization seems an appropriate approach to produce NP with greater colloidal stability and enhanced functionality. The zinc release data from the LDH matrix (2.96 % ±0.002 ppm) showed the effectiveness of the coating in acid medium (pH 1.2) and the release data from GLIB showed the kinetics of release of zero order with release in simulated intestinal medium (pH 7.4) of 88 % and 73 % (24 h) for uncoated and coated NP, respectively. All NP were considered biocompatible in the WST-1 assay on BALB 3T3 fibroblast strains making these NP promising therapeutically.

Glibenclamide nanosuspension inhaler: development, in vitro and in vivo assessment.

Objective: The development of nanosuspension for targeted delivery of glibenclamide as hypoglycemic agent to the lung in an inhaler dosage form.Method: Glibenclamide nanosuspension formulations were prepared using Box-Behnken design to investigate the effect of independent factors on the dependent variables, Fourier-transform Infrared spectroscopy, Differential Scanning Calorimetry, evaluation of glibenclamide nanosuspension inhaler and in vivo hypoglycemic efficacy were performed to determine glibenclamide nanosuspension inhaler effect.Results: The results revealed that the mean particle sizes of the prepared nanosuspension ranged from 0.216 to 0.856 µm, zeta potential from +9 to +16 mV, the solubility ranged from 43% to 75%, the mass median aerodynamic diameter was 2.34 µm and the glucose level in rat was significantly reduced by about 60%.Conclusion: These results confirmed that glibenclamide nanosuspension inhaler enhance hypoglycemic effectiveness and reduce adverse effect of glibenclamide, opening up new dosage form in Diabetes mellitus treatment.

An inner filter effect based sensing system for the determination of caffeine in beverage samples.

In this work, the inner filter effect (IFE) of caffeine (CF) over the fluorescence signal of glibenclamide (GLB) was used for the determination of CF in beverage samples. The system worked in a turn-off mode since the absorption spectrum of CF overlaps the excitation band of GLB resulting in a decline in its fluorescence signal (λexc = 234 nm, λem = 350 nm). No changes in the fluorescence lifetime of GLB (0.29 ns) were observed in the presence of CF up to 127.6 mg L-1 concentration. The parameters that affect the fluorescence intensity were investigated, such as fluorophore concentration (16 mg L-1), pH (3.2) and temperature (25 °C). Under optimized conditions, the IFE-based approach can determine CF in a range between 1.00 and 100.0 mg L-1, with a detection limit (LOD) of 0.10 mg L-1. The relative standard deviation (% RSD) values for the intra-day and inter-day precision were 0.75 and 1.24, respectively. The new method was successfully tested in the determination of the target analyte in beverage samples without previous treatment. The results were compared with those obtained by a reference method, leading to the conclusion that there were no significant differences at the studied confidence level (α = 0.05).

Automated two-step manufacturing of [11C]glyburide radiopharmaceutical for PET imaging in humans.

INTRODUCTION: Glyburide is an approved anti-diabetes drug binding to the sulfonylurea receptors-1 (SUR-1) and substrate of solute carrier (SLC) transporters, which can be isotopically radiolabelled with carbon-11 for PET imaging. The aim of this work is to present an original and reproducible automated radiosynthesis of [11C]glyburide and a full European Pharmacopeia 9.7 compliant quality control to use [11C]glyburide in PET imaging clinical trials. METHODS: Different conditions were explored to afford non-radioactive glyburide by one or two-step methylation. These experiments were monitored by UPLC-MS. The optimized process was applied to the automated radiosynthesis of [11C]glyburide using a TRACERlab® FX C Pro. A complete quality control according to Pharmacopeia guidelines was realized. RESULTS: One-step methylation revealed regioselectivity issues as methylation occurred preferentially on the sulfonylurea moiety. Two-step approach by methylation followed by reaction with cyclohexyl isocyanate afforded glyburide without formation of methylated side products. Ready-to-inject [11C]glyburide was obtained in 5% non-decay corrected radiochemical yield and 110 ±â€¯20 GBq/µmol molar activity within 40 min (n = 8). [11C]Glyburide quality control was compliant with the Pharmacopeia requirements. CONCLUSIONS: We have described a highly reproducible and automated two-step radiosynthesis of [11C]glyburide which was qualified as a radiopharmaceutical for human injection. This whole manufacturing process is currently being used to conduct a clinical trial to elucidate the hepatic transport of drugs. ADVANCES IN KNOWLEDGE: Compared to previously reported radiosynthesis of [11C]glyburide, this work provides an original and reproducible approach which can be transferred to any PET centre interested in using this radiotracer for preclinical or clinical imaging. IMPLICATION FOR PATIENT CARE: This work provides a method to manufacture [11C]glyburide for human PET imaging. This radiopharmaceutical could be used to elucidate the role of transporters in drug exposure of different organs or to monitor brain recovery after central nervous system (CNS) injuries.

Curative Effect of Catechin Isolated from Elaeagnus Umbellata Thunb. Berries for Diabetes and Related Complications in Streptozotocin-Induced Diabetic Rats Model.

In this study, catechin (CTN) isolated from Elaeagnus umbellata was evaluated for in vitro antioxidant potential and inhibition of carbohydrate digestive enzymes (α-amylase and α-glucosidase). The compound was also tested for its in vivo antidiabetic potential using Sprague-Dawley rats as experimental animals. The effects of various doses of catechin in STZ (Streptozotocin) induced diabetic rats on fasting blood glucose level, body weight, lipid parameters, hepatic enzymes, and renal functions were evaluated using the reported protocols. The CTN exhibited the highest percent antioxidant for free radical scavenging activity against DPPH and ABTS free radicals, and inhibited the activity of carbohydrate digestive enzymes (with percent inhibition values: 79 ± 1.5% α-amylase and 80 ± 1.1% α-glucosidase). Administration CTN and standard glibenclamide significantly decreased the fasting blood glucose level and increased the body weight in STZ-induced diabetic rats. CTN significantly decreased the different lipid parameters, hepatic, and renal function enzyme levels along with Hb1c level in diabetic rats, while significantly increasing the high-density lipoprotein (HDL) level with values comparable to the standard glibenclamide. Further, the altered levels of glutathione and lipid peroxides of liver and kidney tissues were restored (by CTN) to levels similar to the control group. CTN significantly increased the antioxidant enzyme activities, total content of reduced glutathione, and reduced the malondialdehyde (MDA) level in rat liver and kidney tissues homogenates, and also corrected the histopathological abnormalities, suggesting its antioxidant potential.

Incorporation of HPMCAS during loading of glibenclamide onto mesoporous silica improves dissolution and inhibits precipitation.

Mesoporous silica has emerged as an enabling formulation for poorly soluble active pharmaceutical ingredients (APIs). Unlike other formulations, mesoporous silica typically does not inhibit precipitation of supersaturated API therefore, a suitable precipitation inhibitor (PI) should be added to increase absorption from the gastrointestinal (GI) tract. However, there is limited research about optimal processes for combining PIs with silica formulations. Typically, the PI is added by simply blending the API-loaded silica mechanically with the selected PI. This has the drawback of an additional blending step and may also not be optimal with regard to release of drug and PI. By contrast, loading PI simultaneously with the API onto mesoporous silica, i.e. co-incorporation, is attractive from both a performance and practical perspective. The aim of this study was to demonstrate the utility of a co-incorporation approach for combining PIs with silica formulations, and to develop a mechanistic rationale for improvement of the performance of silica formulations using the co-incorporation approach. The results indicate that co-incorporating HPMCAS with glibenclamide onto silica significantly improved the extent and duration of drug supersaturation in single-medium and transfer dissolution experiments. Extensive spectroscopic characterization of the formulation revealed that the improved performance was related to the formation of drug-polymer interactions already in the solid state; the immobilization of API-loaded silica on HPMCAS plates, which prevents premature release and precipitation of API; and drug-polymer proximity on disintegration of the formulation, allowing for rapid onset of precipitation inhibition. The data suggests that co-incorporating the PI with the API is appealing for silica formulations from both a practical and formulation performance perspective.

Effect of berberine on in vitro metabolism of sulfonylureas: A herb-drug interactions study.

Patients with type 2 diabetes may co-ingest herbal and prescription medicines to control their blood sugar levels. Competitive binding of drug and herb may mutually affect their metabolism. This can alter the level of drug and its kinetics in the body, potentially causing toxicities or loss of efficacy. Understanding how the metabolism of sulfonylureas like glyburide and gliclazide can be affected by the presence of berberine and vice versa can provide valuable information on the possible risk of toxicities caused by co-ingestion of drugs. METHODS: Berberine and sulfonylureas (glyburide and gliclazide) were co-incubated with rat liver microsomes in the presence of a NADPH-regenerating system. The metabolites of berberine and sulfonylureas were analysed using liquid chromatography with high-resolution mass spectrometry in the positive ion mode. The role of individual isozymes in the metabolism of berberine, glyburide and gliclazide was investigated by using specific inhibitors. RESULTS: In vitro metabolism of berberine led to the formation of demethyleneberberine (B1a) and its isomer B1b through demethylenation. Berberrubine (B2a) and its isomer B2b were formed through demethylation. The isozymes CYP3A and CYP2D were found to be involved in the metabolism of berberine. In vitro metabolism of glyburide and gliclazide led to the formation of hydroxylated metabolites. The isozymes CYP3A and CYP2C were found to be involved in the metabolism of glyburide. Gliclazide was metabolised by CYP2C. In vitro co-incubation of glyburide or gliclazide with berberine showed that each drug's metabolism was compromised as they share a common isozyme. A strong negative linear correlation of glyburide or gliclazide metabolite levels and the concentration of berberine confirmed the effect of berberine on the metabolism of sulfonylureas. CONCLUSIONS: The metabolism of sulfonylureas and berberine was affected when these compounds were co-incubated with each other. This may be attributable to competitive binding of the herb and drug to the catalytic sites of the same isozymes.

Modeling Recrystallization Kinetics Following the Dissolution of Amorphous Drugs.

Amorphous phases are frequently employed to overcome the solubility limitation that is nowadays commonplace in developmental small-molecule drugs intended for oral administration. However, since the solubility enhancement has finite longevity (it is a "kinetic solubility" effect), characterizing its duration (i.e., the so-called "parachute" effect) can be important for optimizing a formulation with regard to its in vivo exposure. Two semiempirical models, based on dispersive kinetics theory, are evaluated for their ability to precisely describe experimental transients depicting a loss in supersaturation (initially generated by the dissolution of the amorphous phase) over time, as the solubilized drug recrystallizes. It is found that in cases where the drug solubility significantly exceeds that of the crystal at longer times, the mechanism has substantial "denucleation" (dissolution) character. On the other hand, "nucleation and growth" (recrystallization) kinetics best describe systems in which the recrystallization goes to completion within the experimental time frame. Kinetic solubility profiles taken from the recent literature are modeled for the following drugs: glibenclamide, indomethacin, loratadine, and terfenadine. In the last case, a combination of three different kinetic models, two classical ones plus the dispersive model, are used together in describing the entire dissolution-recrystallization transient of the drug, obtaining a fit of R2 = 0.993. By precisely characterizing the duration of the "parachute" in vitro (e.g., under biorelevant conditions), the proposed models can be useful in predicting trends and thereby guiding formulation development and optimization.