Computational studies for pre-evaluation of pharmacological profile of gut microbiota-produced gliclazide metabolites.

Background: Gliclazide, a second-generation sulfonylurea derivative still widely used as a second-line treatment for type 2 diabetes mellitus, is well known to be subject to interindividual differences in bioavailability, leading to variations in therapeutic responses among patients. Distinct gut microbiota profiles among individuals are one of the most crucial yet commonly overlooked factors contributing to the variable bioavailability of numerous drugs. In light of the shift towards a more patient-centered approach in diabetes treatment, this study aimed to conduct a pharmacoinformatic analysis of gliclazide metabolites produced by gut microbiota and assess their docking potential with the SUR1 receptor to identify compounds with improved pharmacological profiles compared to the parent drug.

Drug interference with biochemical laboratory tests.

Clinical laboratory practice represents an essential part of clinical decision-making, as it influences 60-70% of medical decisions at all levels of health care. Results of biochemical laboratory tests (BLTs) have a key role in establishment of adequate diagnosis as well as in evaluation of treatment progress and outcome. The prevalence of drug-laboratory test interactions (DLTIs) is up to 43% of patients who had laboratory results influenced by drugs.

Bioaccumulation and biotransformation of simvastatin in probiotic bacteria: A step towards better understanding of drug-bile acids-microbiome interactions.

Although pharmacogenetics and pharmacogenomics have been at the forefront of research aimed at finding novel personalized therapies, the focus of research has recently extended to the potential of intestinal microbiota to affect drug efficacy. Complex interplay of gut microbiota with bile acids may have significant repercussions on drug pharmacokinetics. However, far too little attention has been paid to the potential implication of gut microbiota and bile acids in simvastatin response which is characterized by large interindividual variations.

Antimetastatic Potential of Quercetin Analogues with Improved Pharmacokinetic Profile: A Pharmacoinformatic Preliminary Study.

Background: Urokinase-type plasminogen activator (uPA) system is a crucial pathway for tumor invasion and metastasis. Recently, multiple anticancer effects of quercetin have been described, including inhibitory activity against uPA. However, the clinical use of this flavonoid has been limited due to its low oral bioavailability.

PAMPA model of gliclazide permeability: The impact of probiotic bacteria and bile acids.

Gut microbiota and bile acids possess the ability to modify absorption and pharmacokinetic profile of numerous drugs. Since the variability of gliclazide response in patients cannot be explained only by genetic factors, the influence of gut microbiota and bile acids should be considered. The aim of this study was to determine the effects of probiotic bacteria and bile acids on the gliclazide permeability.

In silico Discovery of Resveratrol Analogues as Potential Agents in Treatment of Metabolic Disorders.

Background: Resveratrol was demonstrated to act as partial agonist of PPAR-γ receptor, which opens up the possibility for its use in the treatment of metabolic disorders. Considering the poor bioavailability of resveratrol, particularly due to its low aqueous solubility, we aimed to identify analogues of resveratrol with improved pharmacokinetic properties and higher binding affinities towards PPAR-γ.

Methods: 3D structures of resveratrol and its analogues were retrieved from ZINC database, while PPAR-γ structure was obtained from Protein Data Bank.

DPP-4 Inhibitors: Renoprotective Potential and Pharmacokinetics in Type 2 Diabetes Mellitus Patients with Renal Impairment.

The continuously increasing incidence of diabetes worldwide has attracted the attention of the scientific community and driven the development of a novel class of antidiabetic drugs that can be safely and effectively used in diabetic patients. Of particular interest in this context are complications associated with diabetes, such as renal impairment, which is the main cause of high cardiovascular morbidity and mortality in diabetic patients. Intensive control of glucose levels and other risk factors associated with diabetes and metabolic syndrome provides the foundations for both preventing and treating diabetic nephropathy.

Pharmacological Applications of Bile Acids and Their Derivatives in the Treatment of Metabolic Syndrome.

Apart from well-known functions of bile acids in digestion and solubilization of lipophilic nutrients and drugs in the small intestine, the emerging evidence from the past two decades identified the role of bile acids as signaling, endocrine molecules that regulate the glucose, lipid, and energy metabolism through complex and intertwined pathways that are largely mediated by activation of nuclear receptor farnesoid X receptor (FXR) and cell surface G protein-coupled receptor 1, TGR5 (also known as GPBAR1). Interactions of bile acids with the gut microbiota that result in the altered composition of circulating and intestinal bile acids pool, gut microbiota composition and modified signaling pathways, are further extending the complexity of biological functions of these steroid derivatives. Thus, bile acids signaling pathways have become attractive targets for the treatment of various metabolic diseases and metabolic syndrome opening the new potential avenue in their treatment.

Bile Acids and Their Derivatives as Potential Modifiers of Drug Release and Pharmacokinetic Profiles.

Bile acids have received considerable interest in the drug delivery research due to their peculiar physicochemical properties and biocompatibility. The main advantage of bile acids as drug absorption enhancers is their ability to act as both drug solubilizing and permeation-modifying agents. Therefore, bile acids may improve bioavailability of drugs whose absorption-limiting factors include either poor aqueous solubility or low membrane permeability.

Potential Applications of Gliclazide in Treating Type 1 Diabetes Mellitus: Formulation with Bile Acids and Probiotics.

A major advancement in therapy of type 1 diabetes mellitus (T1DM) is the discovery of new treatment which avoids and even replaces the absolute requirement for injected insulin. The need for multiple drug therapy of comorbidities associated with T1DM increases demand for developing novel therapeutic alternatives with new mechanisms of actions. Compared to other sulphonylurea drugs used in the treatment of type 2 diabetes mellitus, gliclazide exhibits a pleiotropic action outside pancreatic β cells, the so-called extrapancreatic effects, such as antiinflammatory and cellular protective effects, which might be beneficial in the treatment of T1DM.

The Role of Drug Metabolites in the Inhibition of Cytochrome P450 Enzymes.

Following the drug administration, patients are exposed not only to the parent drug itself, but also to the metabolites generated by drug-metabolizing enzymes. The role of drug metabolites in cytochrome P450 (CYP) inhibition and subsequent drug-drug interactions (DDIs) have recently become a topic of considerable interest and scientific debate. The list of metabolites that were found to significantly contribute to clinically relevant DDIs is constantly being expanded and reported in the literature.

Bile Acids as Novel Pharmacological Agents: The Interplay Between Gene Polymorphisms, Epigenetic Factors and Drug Response.

Background: The field of bile acid research has become tremendously active. Bile acids have been shown to act as signaling molecules that are involved in many metabolic processes, but their role in carcinogenesis is also emerging.

Methods: The aim of this review was to summarize the present knowledge in the innovative field of bile acids pharmacology, to reveal the novel mechanisms of their action, particularly focusing on clinically relevant aspects, and to evaluate the role of both genetic and epigenetic variation in genes encoding bile acid-activated receptors in determining the therapy outcome.

Docking-based preliminary study on the interactions of bile acids with drugs at the transporter level in intestinal bacteria.

Objective: The aim of this study was to estimate the binding-affinities of different bile acids towards drug transporters in Lactobacillus acidophilus and Bifidobacterium longum in order to predict the influence of bile acids and probiotics interactions on drug pharmacokinetics.

Materials And Methods: In order to study interactions of bile acids with transporters of intestinal bacteria, molecular-docking step was performed, using SwissDock web-service. For the purpose of comparison, two natural bile acids, cholic acid (CA) and deoxycholic acid (DCA), and one semi-synthetic bile acid, 12-monoketocholic acid (MKC), were studied in parallel.

PHARMACOGENOMIC DETERMINANTS OF RESPONSE TO CARDIOVASCULAR DRUGS.

Cardiovascular diseases are the leading cause of morbidity and mortality worldwide. Despite considerable advances in cardiovascular pharmacology, significant inter-individual variability in response to drugs affects both their efficacy and safety profile. Drug-gene associations have emerged as important factors determining a spectrum of response to therapy.

Bile acid signaling through farnesoid X and TGR5 receptors in hepatobiliary and intestinal diseases.

Background: The well-known functions of bile acids (BAs) are the emulsification and absorption of lipophilic xenobiotics. However, the emerging evidences in the past decade showed that BAs act as signaling molecules that not only autoregulate their own metabolism and enterohepatic recirculation, but also as important regulators of integrative metabolism by activating nuclear and membrane-bound G protein-coupled receptors. The present review was to get insight into the role of maintenance of BA homeostasis and BA signaling pathways in development and management of hepatobiliary and intestinal diseases.

Pleiotropic functions of bile acids mediated by the farnesoid X receptor.

In addition to their well-established role in the digestion and absorption of dietary lipids, bile acids (BAs) are recognized as signalling molecules in a wide range of metabolic processes. Bile acids regulate their own metabolism and enterohepatic circulation by activating the farnesoid X receptor (FXR). BAs have been shown to affect lipid metabolism, to decrease levels of circulating triglycerides, improve hyperglycemia and insulin signalling, directly act on the arterial wall and protect hepatocytes against cholestatic liver injury.

Quantitative real time-polymerase chain reaction method in Bcr-Abl translocation diagnostics.

Purpose: The quantitative real-time polymerase chain reaction (qRT-PCR) is used in the detection of molecular events involved in leukemogenesis, such as the Bcr-Abl gene translocation, the most important factor in the pathogenesis of chronic myeloid leukaemia (CML). The main aim of our study was to test the reproducibility, specificity and sensitivity of the qRT-PCR in the detection of Bcr-Abl gene translocation.

Methods: In complementary (c)DNA, isolated from K562 Bcr-Abl positive cell line, we performed qRT-PCR analysis with Bcr-Abl specific primers.