Search results for "Drug metabolism"
showing 10 items of 103 documents
Elevated risperidone serum concentrations during acute inflammation, two cases
2015
Inflammation-mediated changes in drug metabolism may lead to alterations in the absorption, distribution, and clearance of psychotropic drugs and thus elevate drug levels in blood and lead to intoxications. We report about two patients who developed an up to threefold increase of dose-related serum concentrations of risperidone’s active moiety (risperidone plus 9-hydroxyrisperidone) during acute inflammation indicated by elevated C-reactive protein. The two female patients (aged 56 and 38 years, respectively) had the diagnoses of paranoid schizophrenia and schizoaffective disorder. For both patients, there was a close time-dependent parallel fluctuation of drug levels and C-reactive protei…
Upgrading cytochrome P450 activity in HepG2 cells co-transfected with adenoviral vectors for drug hepatotoxicity assessment
2011
In a number of adverse drug reactions leading to hepatotoxicity, drug metabolism is thought to be involved by the generation of reactive metabolites from non-toxic drugs. The use of hepatoma cell lines, such as HepG2 cell line, for the evaluation of drug-induced hepatotoxicity is hampered by their low cytochrome P450 expression which makes impossible the study of the toxicity produced by bioactivable compounds. Genetically manipulated cells constitute promising tools for hepatotoxicity applications. HepG2 cells were simultaneously transfected with recombinant adenoviruses encoding CYP1A2, CYP2C9 and CYP3A4 to confer them drug-metabolic competence. Upgraded cells (Adv-HepG2) were highly able…
Computer simulations for bioequivalence trials: Selection of analyte in BCS class II and IV drugs with first-pass metabolism, two metabolic pathways …
2018
A semi-physiological two compartment pharmacokinetic model with two active metabolites (primary (PM) and secondary metabolites (SM)) with saturable and non-saturable pre-systemic efflux transporter, intestinal and hepatic metabolism has been developed. The aim of this work is to explore in several scenarios which analyte (parent drug or any of the metabolites) is the most sensitive to changes in drug product performance (i.e. differences in in vivo dissolution) and to make recommendations based on the simulations outcome. A total of 128 scenarios (2 Biopharmaceutics Classification System (BCS) drug types, 2 levels of KM Pgp, in 4 metabolic scenarios at 2 dose levels in 4 quality levels of t…
Human Hepatic Cell Cultures: In Vitro and In Vivo Drug Metabolism
2003
Drug metabolism is the major determinant of drug clearance, and the factor most frequently responsible for inter-individual differences in drug pharmacokinetics. The expression of drug metabolising enzymes shows significant interspecies differences, and variability among human individuals (polymorphic or inducible enzymes) makes the accurate prediction of the metabolism of a new compound in humans difficult. Several key issues need to be addressed at the early stages of drug development to improve drug candidate selection: a) how fast the compound will be metabolised; b) what metabolites will be formed (metabolic profile); c) which enzymes are involved and to what extent; and d) whether dr…
Fluorescence-Based Screening of Cytochrome P450 Activities in Intact Cells
2013
Fluorimetric methods to assess cytochrome P450 (P450) activities that do not require metabolite separation have been developed. These methods make use of non- or low-fluorescent P450 substrates that produce highly fluorescent metabolites in aqueous solutions. The assays are based on the direct incubation of intact cells in culture with appropriate fluorogenic probe substrates, followed by fluorimetric quantification of the product formed and released into incubation medium. We describe a battery of fluorescence assays for rapid measurement of the activity of nine P450s involved in drug metabolism. For each individual P450 activity the probe showing the best properties (highest metabolic rat…
Chronic exposure of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces an obesogenic effect in C57BL/6J mice fed a high fat diet
2017
IF 3.582; International audience; Contaminant involvement in the pathophysiology of obesity is widely recognized. It has been shown that low dose and chronic exposure to endocrine disruptor compounds (EDCs) potentiated diet- induced obesity. High and acute exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a persistent organic pollutant (POP) and an EDC with anti-estrogenic property, causes wasting syndrome . However at lower doses, the TCDD metabolic effects remain poorly understood. We investigated the obesogenic effect during chronic exposure of TCDD at 1μg/kg body weight (bw)/week in adult C57BL/6J mice fed with a high fat diet (HFD) and exposed from 10 to 42 weeks old to TCDD or e…
Fast evaluation of enantioselective drug metabolism by electrophoretically mediated microanalysis: application to fluoxetine metabolism by CYP2D6.
2013
In this work, a capillary electrophoretic methodology for the enantioselective in vitro evaluation of drugs metabolism is applied to the evaluation of fluoxetine (FLX) metabolism by cytochrome 2D6 (CYP2D6). This methodology comprises the in-capillary enzymatic reaction and the chiral separation of FLX and its major metabolite, norfluoxetine enantiomers employing highly sulfated β-CD and the partial filling technique. The methodology employed in this work is a fast way to obtain a first approach of the enantioselective in vitro metabolism of racemic drugs, with the additional advantage of an extremely low consumption of enzymes, CDs and all the reagents involved in the process. Michaelis-Men…
Can Hepatoma Cell Lines be Re-differentiated to be Used in Drug Metabolism Studies?
2013
Knowledge of metabolism, enzymes so far involved, and potential enzyme-inhibiting or enzyme-inducing properties of new compounds is a key issue in drug development. Primary cultured hepatocytes, cytochrome P450 (CYP)-engineered cells and hepatoma cell lines are currently being used for this purpose, but only primary cultures can produce a metabolic profile of a drug similar to that found in vivo and can respond to inducers. Because of their limited accessibility, alternatives to replace human hepatocytes are currently being explored, including the immortalisation of hepatocytes by using different strategies (i.e. SV40 T-large antigen, conditionally immortalised hepatocytes, transfection wi…
Determination of major human cytochrome P450s activities in 96-well plates using liquid chromatography tandem mass spectrometry.
2007
At the early stage of drug discovery, thousands of new chemical entities (NCEs) may be screened before a single candidate can be identified for development. Evaluation of the effect of NCEs on human CYP450 enzyme activities is a key issue in pharmaceutical development as it may explain inter-subject variability, drug-drug interactions, non-linear pharmacokinetics and toxic effects. A liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method has been developed for the fast and routine analysis of major human CYP450s enzyme activities (CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4) in primary hepatocyte cell cultures. The high sensitivity and selectivity of mass …
Strategies to In Vitro Assessment of Major Human CYP Enzyme Activities by Using Liquid Chromatography Tandem Mass Spectrometry
2008
At the early stage of drug discovery, thousands of new chemical entities (NCEs) may be screened before a single candidate can be identified for development. Determining the role of CYP enzymes in the metabolism of a compound and evaluating the effect of NCEs on human CYP activities are key issues in pharmaceutical development as they may explain inter-subject variability, drug-drug interactions, non-linear pharmacokinetics and toxic effects. Reliable methods for determining enzyme activities are needed to characterize an individual CYP enzyme and to obtain a tool for the evaluation of its role in drug metabolism in humans. Different liquid chromatography tandem mass spectrometry methodologi…