Drug Metabolism Letters

BACKGROUND: Linagliptin is prescribed as a dipeptidyl peptidase-4 (DPP-4) inhibitor. Azithromycin is specified as an antibiotic that binds with 23s rRNA of the 50s ribosomal subunit, obstructing the microbial protein synthesis. Our study focuses on the drug-drug interactions of these drugs. OBJECTIVES: The purpose of the study is to understand the bioavailability and physicochemical approaches of Linagliptin and Azithromycin interaction mediated through the strength and nature of the complexation...

BACKGROUND: In the drug development process, an assessment of bioequivalence is an integral part. For the evaluation of generics against the comparator, average bioequivalence approach is the gold standard method. In the recent past, there were many discussions on whether we have the adequate tool to evaluate generics and thereby drug interchangeability (prescribability and switchability) issue is addressed as average bioequivalence approach just considers population mean. Hence, the alternative approaches like population bioequivalence and individual bioequivalence assessment approaches arise as different variances like inter/ intra-subject variance and subject- by-formulation variance along with population mean are considered...

BACKGROUND: In order to avoid drug-induced liver injury (DILI), in vitro assays, which enable the assessment of both metabolic activation and immune reaction processes that ultimately result in DILI, are needed. OBJECTIVE: In this study, recent progress in the application of in vitro assays using cell culture systems is reviewed for potential DILI-causing drugs/xenobiotics and a mechanistic study on DILI, as well as on the limitations of in vitro cell culture systems for DILI research, was carried out...

BACKGROUND: Darolutamide is recently approved for the treatment of non-metastatic castrate resistance prostate cancer. Hitherto, no stereoselective pharmacokinetic data have been published pertaining to darolutamide and its diastereomers in animals or humans. The key aims of the experiment were to examine darolutamide, S,S-darolutamide and S,R-darolutamide with respect to (a) assessment of in vitro metabolic stability and protein binding and (b) characterization of in vivo oral and intravenous pharmacokinetics in mice...

BACKGROUND: Food-drug interactions may lead to suppression or induction drug metabolizing enzymes. Pomegranate is a commonly used fruit in folk medicine all over the world. Data concerning the effect of pomegranate on the activity of UDP-glucuronosyltransferases (UGTs) is scarce. OBJECTIVE: The purpose of this work was to investigate the effect of pomegranate juice ingestion on the transcription of ugt2b1, ugt2a3, and ugt1a9 in the liver and small intestine of male mice...

BACKGROUND: In healthy volunteers, the probe drug method is widely practised to assess the pharmacokinetic mediated herb-drug interactions (HDI). We analyzed the clinical evidence of CYP3A4 probe drug, Midazolam. METHODS: Literatures where Midazolam was used as a probe drug for prediction of herb-drug interaction was survey through an online database such as google scholar, Scopus, Cochrane, PubMed and clinicaltrials.gov. RESULTS: Midazolam was considered as a sensitive probe for CYP3A4 substrates due to its bioavailability...

BACKGROUND: Saini et al. recently investigated the pharmacokinetics of darolutamide and its diastereomers in vitro and in vivo in Balb/c mice, reporting higher levels of (S,S)-darolutamide than (S,R)-darolutamide following intravenous or oral dosing, and interconversion of (S,R)-darolutamide to (S,S)-darolutamide. OBJECTIVE: To present our in vitro and in vivo studies of darolutamide pharmacokinetics in mice, which contrast with the findings of Saini et al. Methods: Nude male Balb/c mice were orally dosed for 7 days with 25, 50, or 100 mg/kg of darolutamide twice daily...

PURPOSE: Previous studies have shown catabolism of adenosine 5'-triphosphate (ATP) in systemic blood is a potential surrogate biomarker for cardiovascular toxicity. We compared the acute toxicity of high doses of doxorubicin (DOX) and isoproterenol (ISO) on hemodynamics and ATP catabolism in systemic circulation. METHODS: Sprague Dawley (SD) rats (n = 8 - 11) were each given either a single dose of 30 mg/kg ISO, or twice-daily dose of 10 mg/kg of DOX or normal saline (control) for 4 doses by subcutaneous injection...

BACKGROUND: Ezetimibe is a cholesterol lowering agent with an oral bioavailability of 50 % by the virtue of its poor solubility, extensive hepatic and intestinal metabolism. OBJECTIVE: The study is aimed to overcome low bioavailability issues of ezetimibe by formulating an oral disintegrating film. METHOD: The low solubility of ezetimibe was tackled preparing solid dispersions using mannitol, β-cyclodextrin and urea. The mannitol solid dispersion assimilated oral disintegrating film was prepared and optimized using 2 3 factorial design, where concentration of film formers hydroxypropyl methyl cellulose (K5& K15) (X1and X2) and super disintegrant, sodium starch glycolate (X3) was used as factors on the response disintegration time (Y)...

BACKGROUND: CYP450 enzymes in the liver have a significant role in the metabolism of xenobiotics. Probe drug strategy is broadly used to evaluate the pharmacodynamic & pharmacokinetic Drug/ herb-drug interactions/ Fooddrug interactions. Probe drugs guarantee the exact pathway of drug metabolism in the liver by its targeted tractability property. The CYP3A4 isoenzyme metabolizes majority of the drugs (65%). METHODS: The characters of targeted probe drugs were observed from admetSAR (version2) online database...

BACKGROUND: Cytochrome P450 (CYP) contributes to a huge collection of medicinal products' Phase I metabolization. We aimed to summarize and investigate the current evidence regarding the frequency of CYP2D6, CYP2C9, CYP2C19, MDR1 in Saudi Arabia. METHODS: A computerized search in four databases was done using the relevant keywords. Screening process was done in two steps; title and abstract screening and full-text screening. Data of demographic and characteristics of included studies and patients was extracted and tabulated...

BACKGROUND: Carbon-carbon bond cleavage of a saturated aliphatic moiety is rarely seen in xenobiotic metabolism. Olanexidine (Olanedine®), containing an n-octyl (C8) side chain, was mainly metabolized to various shortened side chain (C4 to C6) acid-containing metabolites in vivo in preclinical species. In liver microsomes and S9, the major metabolites of olanexidine were from multi-oxidation on its n-octyl (C8) side chain. However, the carbon-carbon bond cleavage mechanism of n-octyl (C8) side chain, and enzyme(s) responsible for its metabolism in human remained unknown...

BACKGROUND: There have been lack of information of inhibition of bovine medicines on bovine hepatic CYP450 at their commercial doses and dosing routes. OBJECTIVE: This work was to assess inhibition of 43 bovine medicines on bovine hepatic CYP450 using a combination of in vitro assay and Cmax values from pharmacokinetic studies with their commercial doses and dosing routes in literature. METHOD: Those drugs were first evaluated through a single point inhibitory assay at 3 μM in bovine liver microsomes for six specific CYP450 metabolisms, phenacetin o-deethylation, coumarin 7-hydroxylation, tolbutamide 4-hydroxylation, bufuralol 1-hydroxylation, chlorzoxazone 6-hydroxylation and midazolam 1'-hydroxylation...

BACKGROUND: Clinical development of lesinurad, a selective uric acid reabsorption inhibitor, required analysis of lesinurad in plasma from special patient populations. EMA and FDA bioanalytical method validation guidance have recommended studying matrix effects on quantitation if samples from special patient populations are to be analyzed. In addition to lesinurad (plasma protein binding 98.2%), the matrix effects from special population plasma on the quantitation of verapamil (PPB 89...

Advanced medical services and treatments are available for treating Tuberculosis, whose prevalence has increased in recent times. However, the continuous consumption of related drugs is also known for inducing hepatotoxicity which is a critical condition and cannot be overlooked. The present review article has focused on the pathways causing these toxicities and also the role of enzyme CYP2E1 and hepatic glutathione as possible targets which would help inhibit the ongoing adverse effect of hepatotoxicity.

The separation of the brain from blood by the blood-brain barrier and the blood-cerebrospinal fluid (CSF) barrier poses unique challenges for the discovery and development of drugs targeting central nervous system (CNS). This review will describe the role of transporters in CNS penetration and examine the relationship between unbound brain (Cu-brain) and unbound plasma (Cu-plasma) or CSF (CCSF) concentration. Published data demonstrates that the relationship between Cu-brain and Cu-plasma or CCSF can be affected by transporter status and passive permeability of a drug and CCSF may not be a reliable surrogate for CNS penetration...

Cancer cells undergo genetic and environmental changes that can alter cellular disposition of drugs, notably by alterations of transmembrane drug transporters expression. Moreover, drug ionization state can be modified by the hypoxic and acidic surrounding extracellular microenvironment. In Philadelphia-positive leukemia, the drug efflux transporter P-glycoprotein has been well demonstrated to modulate the cell disposition of imatinib, a tyrosine kinase inhibitor targeted to intracellular BCR-ABL oncoprotein...

BACKGROUND: Many CNS drugs have low bioavailability due to their poor water solubility of extensive first-pass metabolism and hence have less effectiveness. OBJECTIVE: The present study aims to enhance the solubility and oral bioavailability of poorly watersoluble antipsychotic drug Amisulpride (AMS) through complexation with 2-hydroxypropyl β- cyclodextrin (HPβCD). It has slow and erratic absorption after oral administration. METHODS: This report describes the study of the phase solubility diagram, preparation of the inclusion complex and tablet of prepared inclusion complex, characterization of the physico-chemical properties of the inclusion complex and tablet...

No abstract text is available yet for this article.

BACKGROUND: Although the liver is the primary organ of drug metabolism, the lungs also contain drug-metabolizing enzymes and may, therefore, contribute to the elimination of drugs. In this investigation, the Precision-cut Lung Slice (PCLS) technique was standardized with the aims of characterizing and comparing rat and human pulmonary drug metabolizing activity. METHOD: Due to the limited availability of human lung tissue, standardization of the PCLS method was performed with rat lung tissue...