RESUMO
A simple and reliable high-performance liquid chromatography method for simultaneous quantitation of gliclazide and ciprofloxacin in plasma sample has been developed and validated. This method implements protein precipitation, a simple and practical pretreatment method by the addition of acetonitrile that gives a clean supernatant. The separation was carried out in a system consisted of a C18 column with acetonitrile and KH2PO4 (0.01 M, 0.1% v/v of triethylamine, pH 2.7) as the mobile phase in a gradient elution at a total flow-rate of 1 mL/min. Gliclazide and ciprofloxacin were quantitated using an ultraviolet detector set at wavelengths of 229 and 277 nm, respectively, which ensures optimal sensitivity for both compounds. This method possesses an excellent linearity at concentration ranges of 0.5-50 mg/L for gliclazide and 0.1-10 mg/L for ciprofloxacin. High within- and between-run accuracy for both gliclazide (% error of -8.00 to 0.45%) and ciprofloxacin (% error of -10.00 to 7.63%) were demonstrated. The intra- and inter-day precision (expressed as %CV) was <8 and 12% for gliclazide and ciprofloxacin, respectively. Both analytes were stable during storage and sample processing. The method reported in this study can be implemented for pharmacokinetic interaction study in rats.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Ciprofloxacina/sangue , Ciprofloxacina/farmacocinética , Gliclazida/sangue , Gliclazida/farmacocinética , Animais , Ciprofloxacina/química , Estabilidade de Medicamentos , Gliclazida/química , Modelos Lineares , Masculino , Ratos , Ratos Wistar , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
AIM: Type 2 diabetes (T2D), as a major cause of morbidity and mortality, is predicted to have a prevalence of 629 million by 2045. As diabetic patients show considerable inter-individual variation in response to antidiabetic treatment, this study aimed to investigate the gene polymorphism of cytochrome P450 as well as the effectiveness and safety of glibenclamide and gliclazide for different genotypes of CYP2C9. Besides, the chronic side effects of T2D including retinal microvasculature complications or retinopathy and renal dysfunction due to nephropathy in different genotypes were considered. PATIENTS AND METHODS: The participants including 80 T2D patients treated with glibenclamide or gliclazide were recruited from university hospitals of Ahvaz Jundishpur University of Medical Sciences, Ahvaz, in the southwest of Iran. Blood samples were collected from the patients at 2.5h after the morning dose of glibenclamide and 12h after the last dose of gliclazide. Genotyping from the extracted DNA was, then, performed using PCR-RFLP. The plasma level of glibenclamide and gliclazide was, in turn, measured by the reverse-phase high-pressure liquid chromatography. RESULTS: The results showed that the wild-type allele, i.e., CYP2C9*1, occurred in the highest frequency (0.8), while the frequency rates of the mutant allele, i.e., CYP2C9*2 and CYP2C9*3, were 0.15 and 0.05, respectively. Moreover, no significant association was found between any of the genotypes as well as the clinical and biochemical characteristics of the patients. The findings also showed that the plasma level of sulfonylureas (i.e., glibenclamide and gliclazide) was the highest in the patients with the CYP2C9*3 allele. It was also found that 75.9% of the patients with variant genotypes had experienced hypoglycemia events. Furthermore, in the absence of wild type allele, a significant increase was observed in retinopathy (p=0.039) and nephropathy (p=0.05). CONCLUSION: The findings can provide guidelines for the optimal management of the treatment protocols with sulfonylurea intended to control the T2D complications.
Assuntos
Glicemia/efeitos dos fármacos , Citocromo P-450 CYP2C9/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/genética , Retinopatia Diabética/genética , Gliclazida/uso terapêutico , Glibureto/uso terapêutico , Hipoglicemiantes/uso terapêutico , Variantes Farmacogenômicos , Biomarcadores/sangue , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/diagnóstico , Retinopatia Diabética/diagnóstico , Feminino , Frequência do Gene , Gliclazida/efeitos adversos , Gliclazida/sangue , Glibureto/efeitos adversos , Glibureto/sangue , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemia/genética , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/sangue , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Resultado do TratamentoRESUMO
This study aimed to investigate the bioequivalence of 2 formulations of gliclazide modified-release tablets 60 mg in 48 healthy Caucasian volunteers under fasting conditions. A test product, Gliclazide MR (Ranbaxy Laboratories Limited, now Sun Pharmaceutical Industries, India), was compared with a reference product, Diamicron MR (Servier, France). The study was performed under a single-dose, 2-treatment, 2-period, 2-sequence crossover design in a fasted condition with a washout period of 21 days. Blood samples were collected for 96 hours after drug administration. Drug plasma concentrations were determined by a liquid chromatography-tandem mass spectrometry method. Analysis of pharmacokinetic characteristics was based on a noncompartmental model. The logarithmically transformed data of Cmax and AUC were analyzed for 90% confidence intervals using analysis of variance. There was no significant difference in pharmacokinetic characteristics between the products, and the 90% confidence intervals were within the acceptance range of 80.00%-125.00%. The investigated products were bioequivalent under fasted conditions.
Assuntos
Gliclazida/farmacocinética , Hipoglicemiantes/farmacocinética , Administração Oral , Adulto , Estudos Cross-Over , Composição de Medicamentos , Jejum/metabolismo , Feminino , Gliclazida/administração & dosagem , Gliclazida/efeitos adversos , Gliclazida/sangue , Voluntários Saudáveis , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/sangue , Masculino , Comprimidos , Equivalência Terapêutica , População Branca , Adulto JovemRESUMO
Type 2 diabetes mellitus is a worldwide health problem. Many drugs can be used in its treatment. One of them is gliclazide - the sulfonylurea derivative. It is dosed in modified release tablets. The study aimed to determine the minimum steady-state concentration of gliclazide at patients taking modified release tablets. Fasting plasma glucose, insulin level, and glycated hemoglobin were also assayed in this study. Ten patients of the primary care physician clinic took 30-90â¯mg of gliclazide daily. The statistical analysis proved that there is a statistically significant correlation between insulin level and body weight (pâ¯=â¯0.044) as well as between the dose and gliclazide concentrations (pâ¯=â¯0.015) and also between insulin level and minimum concentration of the drug (pâ¯=â¯0.0074). The linear correlation between dose and gliclazide's minimum steady state concentration proved its linear pharmacokinetics. The correlation between the minimum concentration of gliclazide and insulin level might be a potential predictor of patients compliance.
Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Gliclazida/administração & dosagem , Hipoglicemiantes/administração & dosagem , Administração Oral , Idoso , Biomarcadores/sangue , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Cálculos da Dosagem de Medicamento , Monitoramento de Medicamentos , Jejum/sangue , Feminino , Gliclazida/sangue , Gliclazida/farmacocinética , Hemoglobinas Glicadas , Humanos , Hipoglicemiantes/sangue , Hipoglicemiantes/farmacocinética , Insulina/sangue , Modelos Lineares , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Modelos Biológicos , Comprimidos , Resultado do TratamentoRESUMO
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.
Assuntos
Gliclazida/farmacologia , Glibureto/farmacologia , Hipoglicemiantes/farmacologia , Canais KATP/antagonistas & inibidores , Albumina Sérica/farmacologia , Animais , Bovinos , Células Cultivadas , Gliclazida/sangue , Gliclazida/metabolismo , Gliclazida/farmacocinética , Glibureto/sangue , Glibureto/metabolismo , Glibureto/farmacocinética , Humanos , Hipoglicemiantes/sangue , Hipoglicemiantes/metabolismo , Hipoglicemiantes/farmacocinética , Insulina/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Técnicas de Patch-Clamp , Ligação Proteica , Proteínas Recombinantes/metabolismo , Albumina Sérica/metabolismo , Soroalbumina Bovina/metabolismo , Soroalbumina Bovina/farmacologia , Xenopus laevisRESUMO
Gliclazide is a second-generation sulphonylurea drug widely used in the treatment of type 2 diabetes. However, there is no single report to describe the population pharmacokinetics of gliclazide in animal models. This study was aimed to evaluate the population pharmacokinetics (PK) of gliclazide in normal and alloxan-induced diabetic rabbits using nonlinear mixed effects modeling. A total of 90 New Zealand white rabbits were administered with three doses (4.13, 8.27 and 16.53 mg/kg b.wt) of gliclazide by an oral route. Blood samples were collected up to 24 hr and the gliclazide concentrations in rabbit were determined using the HPLC method. The non-compartmental and classical compartmental PK analyses were performed using Phoenix WinNonlin. Population PK analysis of gliclazide was performed using nonlinear mixed-effects model software NONMEM and Phoenix NLME considering the weight, age, sex, health and dose as covariates. The final population values for clearance (CL), volume of distribution (V) and the absorption rate constant (ka ) were 5270 ml/hr, 55700 ml and 0.708 hr-1 , respectively. The inter-individual variability in gliclazide CL, V and ka was 16.3%, 14.9% and 26.5%, respectively. There was no significant difference between NONMEM and Phoenix NLME pharmacokinetic results. The visual predictive check and bootstrap analysis confirmed the predictive ability, model stability and precision of the parameter estimates from this model. This population PK model demonstrated that gliclazide pharmacokinetics is best described by one-compartment model with first-order absorption in rabbits. Body weight is a covariate that significantly influences gliclazide kinetic disposition in rabbits.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Gliclazida/farmacocinética , Hipoglicemiantes/farmacocinética , Modelos Biológicos , Animais , Feminino , Gliclazida/sangue , Hipoglicemiantes/sangue , Masculino , Dinâmica não Linear , CoelhosRESUMO
BACKGROUND AND OBJECTIVE: Gliclazide is a drug commonly used in type 2 diabetes mellitus. Recently, gliclazide has shown desirable pharmacological effects such as immunoregulatory and anti-clotting effects, which suggests potential applications in type 1 diabetes mellitus (T1DM). Gliclazide has variable absorption after oral administration, and thus using targeted-delivery techniques, such as microencapsulation, may optimise gliclazide absorption and potential applications in T1DM. Bile acids such as cholic acid have shown microcapsule-stabilising and controlled-release effects, and thus their incorporation into gliclazide microcapsules may further optimise gliclazide release, absorption and antidiabetic effects. Accordingly, this study aimed to examine the hypoglycaemic effects of gliclazide microcapsules with and without cholic acid, in a rat model of T1DM. METHODS: Thirty-five alloxan-induced T1DM rats were randomly divided into five equal groups and gavaged a single dose of empty microcapsules, gliclazide, gliclazide microcapsules, gliclazide-cholic acid or gliclazide-cholic acid microcapsules. Blood samples were collected over 10 h post-dose and analysed for blood glucose and gliclazide serum concentrations. RESULTS: Gliclazide microcapsules exerted a hypoglycaemic effect in the diabetic rats, and cholic acid incorporation diminished the hypoglycaemic effects, which suggests the lack of synergistic effects between gliclazide and cholic acid. In addition, neither microencapsulation nor cholic acid incorporation optimised gliclazide absorption which suggests that hypoglycaemic effects of gliclazide are independent of its absorption and serum concentrations. This also suggests that hypoglycaemic effects of gliclazide may be associated with gut-metabolic activation rather than gut-targeted delivery and systemic absorption. CONCLUSION: Gliclazide microcapsules exerted hypoglycaemic effects in T1DM rats independent of insulin and thus may have potentials in treatment of T1DM.
Assuntos
Ácidos e Sais Biliares/metabolismo , Diabetes Mellitus Tipo 1/tratamento farmacológico , Composição de Medicamentos , Interações Medicamentosas , Gliclazida/farmacologia , Gliclazida/farmacocinética , Hipoglicemiantes/farmacologia , Animais , Glicemia/efeitos dos fármacos , Ácido Cólico/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Gliclazida/administração & dosagem , Gliclazida/sangue , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacocinética , Masculino , RatosRESUMO
Enhancement of the dissolution rate of the poorly water-soluble hypoglycemic agent, gliclazide, by the aid of lyophilization was investigated. Mannitol, sodium lauryl sulfate (SLS) and polyvinyl pyrrolidone (PVP-k-30) were employed in different weight ratios (43%, 56% and 64% w/w, respectively) as water-soluble excipients in the formulation. Lyophilized systems were found to exhibit extremely higher in vitro dissolution rate compared to the unprocessed drug powder. Solid state characterization of the lyophilized systems using X-ray powder diffraction, Fourier transform infrared spectroscopy and differential scanning calorimetry techniques revealed that dissolution enhancement was attributable to transformation of gliclazide from the crystalline to an amorphous state in the solid dispersion formed during the lyophilization process. The gastrointestinal absorption and hypoglycemic effect of the lyophilized gliclazide/SLS system were investigated following oral administration to Albino rabbits. Cmax and area under the plasma concentration-time curve of gliclazide (AUC0-12) after administration of the lyophilized formulations were significantly higher than those obtained after administration of the unprocessed gliclazide.
Assuntos
Excipientes/química , Absorção Gastrointestinal , Gliclazida/farmacocinética , Hipoglicemiantes/farmacocinética , Manitol/química , Povidona/química , Dodecilsulfato de Sódio/química , Animais , Disponibilidade Biológica , Glicemia/análise , Varredura Diferencial de Calorimetria , Fenômenos Químicos , Composição de Medicamentos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Liofilização , Gliclazida/sangue , Gliclazida/química , Gliclazida/farmacologia , Hipoglicemiantes/sangue , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Masculino , Difração de Pó , Coelhos , Espectroscopia de Infravermelho com Transformada de Fourier , SuspensõesRESUMO
In this study, a simple method using microextraction by packed sorbent and high-performance liquid chromatography with ultraviolet detection for simultaneous determination of chlorpropamide, gliclazide and glimepiride in human plasma was developed and validated. A fractional factorial design and a complete factorial design were applied to evaluate the parameters which could affect the extraction and desorption steps, respectively. All parameters in the extraction step (pH, sample volume, sample dilution and number of aspiration/ejection cycles) and in the desorption step (percentage of acetonitrile in the elution solvent and number of aspirations of elution solvent through the device) were statistically significant (p>0.05) when recovery was used as response. The developed method allowed the use of small volumes of sample and solvents and rapid separation by using a fused core column (only 2.2min were needed). This method was fully validated showing selectivity, precision, accuracy and linearity over the range 1.0-50.0µgmL(-1) for chlorpropamide, 1.0-10.0µgmL(-1) for gliclazide and 0.1-1.0µgmL(-1) for glimepiride. Finally, the validated method was applied in the analysis of samples from volunteers containing the three tested analytes.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Hipoglicemiantes/sangue , Microextração em Fase Sólida/métodos , Clorpropamida/sangue , Gliclazida/sangue , Humanos , Concentração de Íons de Hidrogênio , Reprodutibilidade dos Testes , Compostos de Sulfonilureia/sangueRESUMO
Gliclazide is practically insoluble in water and its GI absorption is limited by its dissolution rate. Our previously published works indicated that preparing gliclazide-crosspovidone solid dispersion in the drug/ carrier ratio of 1:1 using cogrinding technique is able to enhance drug dissolution rate. The coground of gliclazide-crosspovidone was administrated to the rats and the hypoglycemic effects of pure drug, a physical mixture and the coground were considered in 3 groups of rats weighing 200-250 g (n=6). The rats were made diabetic by single intravenous administration of streptozotocin (60 mg/kg). Each of the rats received a single dose of gliclazide (equivalent to 40 mg/kg) as pure drug, physical mixture and coground in an aqueous suspension. Glucose level was assessed via glucometer after collecting the blood samples from tail vein. Gliclazide concentration in plasma was assessed applying high pressure liquid chromatography. According to 1-way ANOVA, Student-Newman-Keuls test, the coground revealed enhanced hypoglycemic effects as well as higher serum gliclazide concentration relative to pure drug and its corresponding physical mixture in the all sampling times. The area under serum glucose concentration curve vs. time for the pure gliclazide, physical mixture and coground formulations were 3 090.5±79, 3 018.8±96 and 2 374.0±73 mg.h/dl, respectively. Correspondingly, their area under serum gliclazide concentration curve vs. time were 1 171.8±156.8, 1 379.5±96.2 and 4 827.7±637.5 µg.h/ml. It follows that; formulation of gliclazide-crosspovidone coground is able to improve oral absorption of the drug.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Gliclazida/uso terapêutico , Hipoglicemiantes/uso terapêutico , Animais , Glicemia/análise , Diabetes Mellitus Experimental/sangue , Portadores de Fármacos , Gliclazida/sangue , Masculino , Ratos , Solubilidade , EstreptozocinaRESUMO
Green (reagents and organic solvents saving) analytical chemistry is a new strategy for pharmaceutical analysis. The principles of this idea include primary elimination or at least reduction of the amounts of organic reagents and solvents. In this study, we have provided two simple methods for the analysis of clinical drugs in human plasma. One is the capillary LC (Cap LC) connected to MS-MS, the other is the matrix-assisted laser desorption ionization (MALDI) connected to TOF MS. Sulfonylurea drugs are usually used in diabetes mellitus patients. Diabetes is a syndrome of disordered metabolism resulting in abnormally high blood sugar levels (hyperglycemia). These microscale methods were successfully applied for the monitoring of drug levels in human plasma using gliclazide (a second-generation sulfonylurea) as the test platform. The sensitivity of these methods is sufficient for detecting the gliclazide within a therapeutic range. All the analytical procedures (including human plasma, sample preparation, and flow rate of the analytical system) were at microscale level. These two methods would lower the consumption of organic solvents further safeguarding our environment.
Assuntos
Cromatografia Líquida/métodos , Gliclazida/sangue , Hipoglicemiantes/sangue , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida/instrumentação , Gliclazida/química , Química Verde , Humanos , Hipoglicemiantes/química , Estrutura Molecular , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Solventes , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/instrumentação , Espectrometria de Massas em Tandem/instrumentação , Tolbutamida/químicaRESUMO
The aim of this study was to investigate the pharmacokinetics and glucose-lowering activity of gliclazide alone and in combination with the bile acid salt, sodium 3alpha,7alpha-dihydroxy-12-keto-5beta-cholanate (MKC), in a rat model of type I diabetes. Eighty male Wistar rats were divided into eight groups (n=10). Four groups were treated with alloxan (30 mg/kg) to induce diabetes. One group of healthy and one group of diabetic rats were administered gliclazide (20 mg/kg), MKC (4 mg/kg) or a combination of gliclazide (20 mg/kg) and MKC (4 mg/kg). One group of healthy and one group of diabetic rats were used as controls. Blood samples were collected from the tail vein 6 hours post-dose and the plasma was analyzed for glucose concentrations. It was found that gliclazide bioavailability was increased in healthy rats when coadministered with MKC, but there was no difference in glucose levels. Gliclazide bioavailability was much lower in diabetic rats and was not altered by MKC. However, the hypoglycemic effect of the combination of gliclazide and MKC was significantly greater in diabetic rats than that of gliclazide alone. It was demonstrated that the combination of MKC and gliclazide produced a significant hypoglycemic effect in a rat model of Type I diabetes. As gliclazide alone does not have a hypoglycemic effect on Type I diabetic rats, it can be concluded that gliclazide potentiates hypoglycemic effect of MKC in Type I diabetic rats.
Assuntos
Glicemia/metabolismo , Ácido Quenodesoxicólico/análogos & derivados , Diabetes Mellitus Experimental/tratamento farmacológico , Gliclazida/farmacocinética , Hipoglicemiantes/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Glicemia/análise , Ácido Quenodesoxicólico/administração & dosagem , Ácido Quenodesoxicólico/farmacologia , Ácido Quenodesoxicólico/uso terapêutico , Cromatografia Líquida de Alta Pressão , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/metabolismo , Sinergismo Farmacológico , Quimioterapia Combinada , Gliclazida/sangue , Gliclazida/uso terapêutico , Hipoglicemiantes/sangue , Hipoglicemiantes/uso terapêutico , Masculino , Espectrometria de Massas , Ratos , Ratos Wistar , Resultado do TratamentoRESUMO
A sensitive and selective liquid chromatographic--mass spectrometric (LC-MS) method for the determination of gliclazide (CAS 21187-98-4) in human plasma has been developed. Sample treatment was based on protein precipitation with acetonitrile. Analytical determination was carried out on a C18 column interfaced with a triple quadrupole mass spectrometer. Positive electrospray ionization was employed as the ionization source. The mobile phase was acetonitrile-water containing 10 mmol/l ammonium acetate, pH 3.5 adjusted with acetic acid (75:25) at the flow rate of 1.0 ml/min. Both the analyte and the internal standard glipizide (CAS 29094-61-9) were detected by use of selected ion monitoring mode. The method was linear in the concentration range of 0.025-2.5 microg/mL. The lower limit of quantification (LLOQ) was 0.025 microg/mL. The intra- and inter-day relative standard deviation across three validation runs over the entire concentration range was less than 9.8%. The accuracy determined at three concentrations (0.05, 0.2 and 1.5 microg/mL for gliclazide) was within +/- 10.11% in terms of relative error (RE). The method herein described was successfully applied for the evaluation of pharmacokinetic profiles of gliclazide sustained release tablets in 18 healthy volunteers. The results show that AUC, Tmax, Cmax and T1/2 between the test formulation and reference formulation have no significant difference (P > 0.05). Relative bioavailability is 96.7.4 +/- 12.9%.
Assuntos
Gliclazida/sangue , Gliclazida/farmacocinética , Hipoglicemiantes/sangue , Hipoglicemiantes/farmacocinética , Disponibilidade Biológica , Calibragem , Cromatografia Líquida de Alta Pressão , Preparações de Ação Retardada , Gliclazida/administração & dosagem , Humanos , Concentração de Íons de Hidrogênio , Hipoglicemiantes/administração & dosagem , Controle de Qualidade , Padrões de Referência , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
OBJECTIVE: Gliclazide is a potent antidiabetic agent because of its capability to decrease blood glucose level via stimulating endogenous insulin secretion from beta-pancreas cells. Gliclazide is insoluble in water and has low dissolution rate. In this study, polyethylene glycol (PEG) 6000 was used as a matrix to disperse gliclazide in the solid state, and the pharmacokinetic profile of this solid dispersion was studied in rats. DESIGN: The solid dispersion of Gliclazide:PEG 6000 (1:4) was prepared by solvent evaporation method. MAIN OUTCOME MEASURES: Samples characterization included differential scanning calorimetry (DSC), infrared spectroscopy (IR), X-ray diffraction (XRD), and solubility and dissolution test. In vivo study was carried out in healthy rats, randomly. After a single dose of oral administration, blood samples were collected pre-dose (15 min before) and 1, 2, 3, 4, 5, 6, 8, 10, and 12 h post-dose. Plasma concentration of gliclazide was determined by high pressure liquid chromatography method using C-18 column, with mobile phase KH2PO4 (pH 4.6)-acetonitril (40:60 v/v) and UV detection at 229 nm. RESULTS: Results showed that there were no differences in DSC, IR spectroscopy, XRD, and dissolution test between the solid dispersion and physical mixture. In vivo data showed that the Tmax of gliclazide in solid dispersion and physical mixture was significantly decreased, while the Cmax, AUC(0-12), and AUC(0-infinity) were significantly increased compared to gliclazide alone. These results indicate that the rapid Tmax was due to rapid absorption of gliclazid across the GI tract membrane. Increased Cmax, AUC(0-12), and AUC(0-infinity) indicate a better absorption of gliclazide in solid dispersion and physical mixture than of gliclazide alone. CONCLUSION: Increased in gliclazide dissolution in the presence of PEG 6000 was followed by improved in vivo data.
Assuntos
Portadores de Fármacos , Gliclazida/farmacocinética , Hipoglicemiantes/farmacocinética , Polietilenoglicóis/química , Administração Oral , Animais , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Química Farmacêutica , Cristalografia por Raios X , Composição de Medicamentos , Gliclazida/administração & dosagem , Gliclazida/sangue , Gliclazida/química , Concentração de Íons de Hidrogênio , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/sangue , Hipoglicemiantes/química , Masculino , Difração de Pó , Ratos , Ratos Wistar , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Tecnologia Farmacêutica/métodos , MolhabilidadeRESUMO
The aim of this study was to perform an in-vitro-in-vivo correlation (IVIVC) for two 60-mg gliclazide extended-release formulations (Fast and Slow release) given once a day and to compare their plasma concentrations over time. In-vitro release rate data were obtained for each formulation using the USP apparatus II, paddle stirrer at 50 and 100 rev min(-1) in 0.1 M HCl and pH 7.4 phosphate buffer. The similarity factor (f2) was used to analyse the dissolution data. Eighteen healthy subjects participated in the study, conducted according to a completely randomized, two-way crossover design. The formulations were compared using area under the plasma concentration-time curve, AUC(0-infinity), time to reach peak plasma concentration, Tmax, and peak plasma concentration Cmax, while correlation was determined between in-vitro release and in-vivo absorption. A linear correlation model was developed using percent absorbed data versus percent dissolved data from the two formulations. Predicted gliclazide concentrations were obtained by use of a curve fitting equation. Prediction errors were estimated for Cmax and area under the curve AUC(0-infinity) to determine the validity of the correlation. 0.1 M HCl at 50 rev min(-1) was found to be the most discriminating dissolution method. Linear regression analysis of the mean percentage of dose absorbed versus the mean percentage of in-vitro release resulted in a significant correlation (r2 > 0.98) for the two formulations. An average percent prediction error for Cmax was 4.15% for Fast release and 3.99% for Slow release formulation whereas for AUC(0-infinity) it was 6.36% and 4.66% for Fast release and Slow release formulation, respectively.
Assuntos
Gliclazida/administração & dosagem , Gliclazida/farmacocinética , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacocinética , Área Sob a Curva , Disponibilidade Biológica , Química Farmacêutica , Estudos Cross-Over , Preparações de Ação Retardada , Gliclazida/sangue , Humanos , Hipoglicemiantes/sangue , Masculino , Modelos Biológicos , Análise de Regressão , Reprodutibilidade dos Testes , Solubilidade , ComprimidosRESUMO
The relationship between the pharmacokinetics of gliclazide and its antidiabetic efficacy were evaluated on the basis of experimental determination of changes with time in the plasma levels of this antidiabetic agent and those of glucose. The experiment included rats with both initial normal glycaemia and alloxan-induced hyperglycaemia (glycaemia increased by a minimum of 30%). Pharmacokinetic and pharmacodynamic parameters were examined in the interval of 30 to 180 min after p.o. administration of a single dose of 25 mg/kg of gliclazide. The drug was administered on day 4, following a single i.v. dose of either 50 mg/kg of alloxan (hyperglycaemic group) or the injection vehicle (control group). Even though the biological availability of gliclazide was similar in both normoglycaemic and hyperglycaemic animals, the gliclazide-induced hypoglycaemizing response was not uniform: until 60 min, the decrease of glycaemia was smaller in animals with alloxan hyperglycaemia (23% decrease at 60 min) in contrast to the normoglycaemic animals (36% decrease at 60 min), at later times, the intensity of this hypoglycaemizing effect of gliclazide persisted in the hyperglycaemic animals, while in the normoglycaemic ones, a reversal of the hypoglycaemizing effect occurred.
Assuntos
Gliclazida/farmacocinética , Hiperglicemia/tratamento farmacológico , Administração Oral , Aloxano/administração & dosagem , Aloxano/toxicidade , Animais , Área Sob a Curva , Glicemia/metabolismo , Cromatografia Líquida de Alta Pressão , Gliclazida/sangue , Gliclazida/uso terapêutico , Hiperglicemia/sangue , Hiperglicemia/induzido quimicamente , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Injeções Intravenosas , Insulina/sangue , Masculino , Ratos , Ratos Wistar , Fatores de TempoRESUMO
OBJECTIVE: The aim of this study was to evaluate, in human volunteers, the performance of one gliclazide tablet formulation (gliclazide 80 mg tablet from EMS Indústria Farmacêutica Ltda.) against two reference gliclazide tablet formulations (Diamicron 80 mg tablet from Servier do Brazil Ltda. and Diamicron 80 mg tablet from Servier (Ireland) Industries Limited). METHODS: The study had an open, randomized, three-period crossover design with a one-week washout interval between doses. The samples were obtained over a 48-h interval after each oral administration of gliclazide. The samples were extracted from plasma using diethylether : hexane (80 : 20, v/v) and the extracts were analyzed by high-performance liquid chromatography coupled with electrospray tandem mass spectrometry (HPLC-MS/ MS). Chromatography was performed isocratically using a Jones Chromatography Genesis C8 120A 4u. The method had a chromatographic run-time of 2.5 min and a calibration curve of the range of 0.02- 10 microg x ml(-1) (r(2) > 0.9993). The limit of quantification was 0.02 microg x ml(-1). RESULTS: The geometric mean and 90% confidence intervals (CI) for the Gliclazide/Diamicron (Ireland) ratio were 588.68% (90% CI= 491.16, 705.58%) for AUClast, 423.50% (90% CI = 338.25, 530.23%) for AUCinf, and 1395.77% (90% CI= 1116.62, 1744.72%) for Cmax. The geometric mean and 90% confidence intervals (CI) for the Gliclazide/Diamicron (Brazil) ratio were 249.16% (90% CI = 207.96, 298.54%) for AUCiast, 249.16% (90% CI = 207.96 - 298.54%) for AUCinf, and 188.04% (90% CI - 151.72, 233.05%) for Cmax. CONCLUSION: Since the 90% CI for Cmax, AUClast and AUC(0-infinity) ratios were all outside the 125% interval proposed by the US Food and Drug Administration, we concluded that the gliclazide test formulation were not bioequivalent to either reference formulation. Interestingly, the pharmacokinetic parameters such as Cmax, AUClast of both reference formulations are compatible with neither the literature nor the profile of an immediate release formulation. In addition, both reference formulations were not bioequivalent in themselves, indicating significant differences in reference product formulation.
Assuntos
Gliclazida/farmacocinética , Hipoglicemiantes/farmacocinética , Adulto , Cromatografia Líquida de Alta Pressão , Estudos Cross-Over , Diabetes Mellitus Tipo 2 , Estabilidade de Medicamentos , Feminino , Gliclazida/sangue , Humanos , Hipoglicemiantes/sangue , Masculino , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem , Equivalência TerapêuticaRESUMO
AIMS: To investigate the influence of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics of gliclazide modified release (MR) in healthy Chinese subjects. METHODS: In a single-dose pharmacokinetic study, 24 healthy male subjects with various CYP2C9 and CYP2C19 genotypes received an oral dose of 30 mg gliclazide MR and plasma was sampled for 72 h postdose. In a multiple-dose pharmacokinetic study, 17 other CYP2C9*1 homozygotes with various CYP2C19 genotypes received 30 mg gliclazide MR once daily for 6 days and plasma was sampled after the last dose. The plasma concentrations of gliclazide were measured using a validated LC/MS/MS method. CYP2C9 and CYP2C19 genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: In the single-dose study, no significant difference in any pharmacokinetic parameters was found in CYP2C9*1/*1, *1/*3 and *1/*13 subjects. In contrast, the AUC(0-infinity) of gliclazide was significantly increased by 3.4-fold [95% confidence interval (CI) 2.5, 4.7; P < 0.01] in CYP2C19 poor metabolizer (PM) subjects compared with CYP2C19*1 homozygotes. The half-life (t(1/2)) was prolonged from 15.1 to 44.5 h (P < 0.01). Similar differences were found in the multiple-dose study. The parameters of gliclazide AUC(ss), AUC(0-infinity) and C(max) were 3.4-fold (95% CI 2.9, 4.0), 4.5-fold (95% CI 3.8, 5.4) and 2.9-fold (95% CI 2.4, 3.4) increased (P < 0.01) in CYP2C19 PM subjects, respectively, compared with CYP2C19*1 homozygotes, and t(1/2) was increased from 13.5 to 24.6 h (P < 0.01). CONCLUSIONS: The pharmacokinetics of gliclazide MR are affected mainly by CYP2C19 genetic polymorphism instead of CYP2C9 genetic polymorphism.
Assuntos
Glicemia/metabolismo , Gliclazida/farmacocinética , Hipoglicemiantes/farmacocinética , Adulto , Hidrocarboneto de Aril Hidroxilases/genética , Povo Asiático/genética , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP2C9 , Relação Dose-Resposta a Droga , Genótipo , Gliclazida/sangue , Humanos , Hipoglicemiantes/sangue , Masculino , Oxigenases de Função Mista/genética , Polimorfismo GenéticoRESUMO
To be able to estimate accurately parameters entering a non-linear mixed effects model taking into account that one or more subpopulations of patients can exist rather than assuming that the entire population is best described by unimodal distributions for the random effects, we proposed a methodology based on the likelihood approximation using the Gauss-Hermite quadrature. The idea is to combine the estimation of the model parameters and the detection of homogeneous subgroups of patients in a given population using a Gaussian mixture for the distribution of the random effects. As the accuracy of the likelihood approximation is likely to govern the quality of the estimation of the different parameters entering the non-linear mixed effects model, we based this approximation on the use of an adjustable Gauss-Hermite quadrature. Moreover, to complete this methodology, we propose a strategy allowing the detection and explanation of heterogeneity based on the Kullback-Leibler test, which was used to estimate the number of components in the Gaussian mixture. In order to evaluate the capability of the method to take into account heterogeneity, this strategy was performed in a PK/PD analysis using the database and the structural model selected in a previous analysis. In this analysis, non-responders were found out using NONMEM [Beal and Sheiner. NONMEM Users Guides. NONMEM Project Group, University of California, San Francisio, 1992] in a population of diabetic patients treated with a once-a-day new formulation of an antidiabetic drug. The authors looked for a subpopulation of patients for whom the therapeutic effect would vanish. In this paper, we looked for subpopulations of patients exhibiting specificities with respect to different parameters entering the description of the effect. The results obtained with our approach are compared in terms of parameter estimation and heterogeneity detection to those obtained in the previous analysis.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Gliclazida/farmacocinética , Gliclazida/uso terapêutico , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Modelos Biológicos , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Gliclazida/sangue , Humanos , Hipoglicemiantes/sangue , Funções Verossimilhança , Dinâmica não Linear , Distribuição Normal , Reprodutibilidade dos Testes , Resultado do TratamentoRESUMO
A simple, rapid and sensitive isocratic reversed phase HPLC method with UV detection using a monolithic column has been developed and validated for the determination of gliclazide in human plasma. The assay enables the measurement of gliclazide for therapeutic drug monitoring with a minimum quantification limit of 10ngml(-1). The method involves simple, one-step extraction procedure and analytical recovery was complete. The separation was carried out in reversed-phase conditions using a Chromolith Performance (RP-18e, 100mmx4.6mm) column with an isocratic mobile phase consisting of 0.01M disodium hydrogen phosphate buffer-acetonitrile (52:48, v/v) adjusted to pH 4.0. The wavelength was set at 230nm. The calibration curve was linear over the concentration range 10-5000ngml(-1). The coefficients of variation for inter-day and intra-day assay were found to be less than 6.0%.