Phenotyping of cytochrome P450 2E1 in vitro and in vivo.

Abstract:

:The aim of the present study was to develop and improve methods for phenotyping of CYP2E1, an important enzyme in the biotransformation of many industrial chemicals, therapeutic drugs and endogenous substances. The possibility to measure CYP2E1 activity in lymphocytes by using p-nitrophenol as a substrate and CYP2E1 protein levels by flow cytometry were studied in vitro. Further, the conventional chlorzoxazone method for in vivo phenotyping was studied by adjusting the dose to body weight in 10 healthy volunteers. Finally, the possibility to obtain the chlorzoxazone metabolic ratio in saliva samples was investigated. No CYP2E1 protein in lymphocytes was detected by using flow cytometry. Some enzyme activity was found in the experiments with p-nitrophenol, however, it could not be verified that it was catalyzed by CYP2E1. Chlorzoxazone and 6-hydroxychlorzoxazone were not detectable in saliva samples. The present in vivo experiments, combined with our previous data (in total 356 experiments in 50 subjects) show that the metabolic ratio increases with decreasing absorbed dose, expressed as the sum of chlorzoxazone and 6-hydroxychlorzoxazone in plasma at 2 h. The increase becomes pronounced at sum concentrations below 100 microM. In conclusion, chlorzoxazone metabolism in vivo remains the only available method for CYP2E1 phenotyping. The administered dose as well as the absorption of the probe influences the chlorzoxazone ratio. We suggest that a dose of 10 mg chlorzoxazone per kg body weight is used to estimate the CYP2E1 phenotype. Further, metabolic ratios should be disregarded if the sum of plasma chlorzoxazone and 6-hydroxychlorzoxazone is below 100 microM (blood sampled after 2 h).

journal_name

Curr Drug Metab

journal_title

Current drug metabolism

authors

Ernstgård L,Johanson G,Karlsson AS,Warholm M

doi

10.2174/138920007780866843

subject

Has Abstract

pub_date

2007-06-01 00:00:00

pages

493-8

issue

5

eissn

1389-2002

issn

1875-5453

journal_volume

8

pub_type

临床试验,杂志文章
  • Gold Nanoparticles: Promising Agent to Improve the Diagnosis and Therapy of Cancer.

    abstract:BACKGROUND:Gold nanoparticles have been exploited for nanobiotechnology applications for the last two decades. New insights of the nanomaterials as promising agent for cancer diagnosis and therapy have just started to emerge. Due to the size- and shape-dependent optical, electrical and thermal properties, gold nanopart...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审

    doi:10.2174/1389200218666170925122513

    authors: Ning L,Zhu B,Gao T

    更新日期:2017-01-01 00:00:00

  • The Role of Drug Transporters in the Pharmacokinetics of Antibiotics.

    abstract:BACKGROUND:Various transporters, including efflux transporters and uptake transporters, play an important role in the pharmacokinetics of drugs. Currently, studies suggest that several antibiotics also serve as substrates for transporters. In addition, these antibiotics are usually combined with other drugs to treat di...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审

    doi:10.2174/1389200217666160629114449

    authors: Hua WJ,Hua WX,Jian Z,Wei PH,Ni LY,Hua LY,Wen CD,Ying Z,Li C

    更新日期:2016-01-01 00:00:00

  • Metabolism of designer drugs of abuse: an updated review.

    abstract::This paper reviews the metabolism of new designer drugs of abuse that have emerged on the black market during the last years and is an update of a review published in 2005. The presented review contains data concerning the so-called 2C compounds (phenethylamine type) such as 4-bromo-2,5-dimethoxy-beta-phenethylamine (...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审

    doi:10.2174/138920010791526042

    authors: Meyer MR,Maurer HH

    更新日期:2010-06-01 00:00:00

  • Marine Drugs: A Hidden Wealth and a New Epoch for Cancer Management.

    abstract:BACKGROUND:Malignant tumors are the leading cause of death in humans. Due to the tedious efforts and investigations made in the field of marine drug discovery, there is now a scientific bridge between marine and pharmaceutical sciences. However, currently only few marine drugs have been lined towards anticancer directi...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审

    doi:10.2174/1389200218666170221105402

    authors: Shakeel E,Arora D,Jamal QMS,Akhtar S,Khan MKA,Kamal MA,Siddiqui MH,Lohani M,Arif JM

    更新日期:2018-01-01 00:00:00

  • A microscale in vitro physiological model of the liver: predictive screens for drug metabolism and enzyme induction.

    abstract::In vitro models of the liver using isolated primary hepatocytes have been used as screens for measuring the metabolism, toxicity and efficacy of xenobiotics, for studying hepatocyte proliferation, and as bioartificial liver support systems. Yet, primary isolated hepatocytes rapidly lose liver specific functions when m...

    journal_title:Current drug metabolism

    pub_type: 杂志文章

    doi:10.2174/138920005774832632

    authors: Sivaraman A,Leach JK,Townsend S,Iida T,Hogan BJ,Stolz DB,Fry R,Samson LD,Tannenbaum SR,Griffith LG

    更新日期:2005-12-01 00:00:00

  • The recent development of nanoparticles for brain tumor targeting delivery.

    abstract::Superparamagnetic iron oxide nanoparticles (SPIONs) have attracted a lot of interest due to their widespread diagnostic and therapeutic applications in neuro-oncology. Functinalization of the particles surface with targeting molecules that recognize tumor receptors might be exploited for the specific brain tumor targe...

    journal_title:Current drug metabolism

    pub_type: 杂志文章

    doi:

    authors: Shevtsov MA

    更新日期:2016-06-15 00:00:00

  • A Review of Theranostics Applications and Toxicities of Carbon Nanomaterials.

    abstract:BACKGROUND:In the last few years, the use of modified Carbon Nanomaterials (CNMs) for theranostics (therapeutic and diagnosis) applications is a new and rapidly growing area in pharmacy and medical fields. Owing to this, their specific physicochemical behaviors like high stability, drug loading, surface area to volume ...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审

    doi:10.2174/1389200219666180925094515

    authors: Gupta N,Rai DB,Jangid AK,Kulhari H

    更新日期:2019-01-01 00:00:00

  • Species-specific and age-dependent bile acid composition: aspects on CYP8B and CYP4A subfamilies in bile acid biosynthesis.

    abstract::The present review aims to give an overview of the cytochrome P450 8B (CYP8B) and cytochrome P450 4A (CYP4A) subfamilies in relation to biosynthesis of bile acids, in particular trihydroxy bile acids. Trihydroxy bile acids are basically required in most species and have an impact on cholesterol and lipid metabolism. T...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审

    doi:10.2174/138920008784220574

    authors: Lundell K,Wikvall K

    更新日期:2008-05-01 00:00:00

  • Oral L-carnitine: metabolite formation and hemodialysis.

    abstract::L-Carnitine has important roles in intermediary metabolism and patients with end-stage renal disease who are undergoing hemodialysis may develop a secondary L-carnitine deficiency. The extent of accumulation of the metabolites trimethylamine and trimethylamine-N-oxide when L-carnitine is administered orally has not be...

    journal_title:Current drug metabolism

    pub_type: 临床试验,杂志文章

    doi:10.2174/138920006778520561

    authors: Bain MA,Faull R,Milne RW,Evans AM

    更新日期:2006-10-01 00:00:00

  • Cholinesterase reactivators: the fate and effects in the organism poisoned with organophosphates/nerve agents.

    abstract::Understanding the mechanism of action of organophosphates (OP)/nerve agents -- irreversible acetylcholinesterase (AChE, EC 3.1.1.7) inhibition at the cholinergic synapses followed by metabolic dysbalance of the organism -- two therapeutic principles for antidotal treatment are derived. The main drugs are anticholinerg...

    journal_title:Current drug metabolism

    pub_type: 杂志文章

    doi:10.2174/138920007782798144

    authors: Bajgar J,Kuca K,Jun D,Bartosova L,Fusek J

    更新日期:2007-12-01 00:00:00

  • CYP-mediated clozapine interactions: how predictable are they?

    abstract::Despite the introduction of newer drugs, the atypical antipsychotic clozapine remains the most effective drug in psychotic patients who are resistant to treatment with conventional agents. Optimal therapeutic responses to clozapine have been reported with serum concentrations between 350 microg/L and 1000 microg/L. Cl...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审

    doi:10.2174/138920007780655469

    authors: Chetty M,Murray M

    更新日期:2007-05-01 00:00:00

  • Clinical Pharmacokinetics of Propranolol Hydrochloride: A Review.

    abstract:BACKGROUND:Nobel laureate Sir James Black's molecule, propranolol, still has broad potential in cardiovascular diseases, infantile haemangiomas and anxiety. A comprehensive and systematic review of the literature for the summarization of pharmacokinetic parameters would be effective to explore the new safe uses of prop...

    journal_title:Current drug metabolism

    pub_type: 杂志文章

    doi:10.2174/1389200221666200414094644

    authors: Kalam MN,Rasool MF,Rehman AU,Ahmed N

    更新日期:2020-01-01 00:00:00

  • Using Reduced Amino Acid Alphabet and Biological Properties to Analyze and Predict Animal Neurotoxin Protein.

    abstract:AIMS:Because of the high affinity of these animal neurotoxin proteins for some special target site, they were usually used as pharmacological tools and therapeutic agents in medicine to gain deep insights into the function of the nervous system. BACKGROUND AND OBJECTIVE:The animal neurotoxin proteins are one of the mo...

    journal_title:Current drug metabolism

    pub_type: 杂志文章

    doi:10.2174/1389200221666200520090555

    authors: Yu Y,Wang S,Wang Y,Cao Y,Yu C,Pan Y,Su D,Lu Q,Zuo Y,Yang L

    更新日期:2020-01-01 00:00:00

  • LC/MS based tools and strategies on qualitative and quantitative analysis of herbal components in complex matrixes.

    abstract::Accompanying with hot discussions on developing multi-target drugs for the therapy of multi-gene diseases, herbal medicines are receiving more and more attention worldwide in both academic and industrial fields. Pharmacokinetic and metabolic research is one of the important issues for intensive understanding of therap...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审

    doi:10.2174/138920012803341285

    authors: Wu L,Hao H,Wang G

    更新日期:2012-11-01 00:00:00

  • Strong Association between Serotonin Transporter 5-HTTVNTR Variant and Psychoactive Substance (Nicotine) Use in the Turkish Cypriot Population.

    abstract:BACKGROUND:The use of psychoactive substances is one of the most dangerous social problems worldwide. Nicotine dependence results from the interaction between neurobiological, environmental and genetic factors. Serotonin is a neurotransmitter that has a wide range of central nervous system activities. The serotonin tra...

    journal_title:Current drug metabolism

    pub_type: 杂志文章

    doi:10.2174/1389200221666200620201348

    authors: Kandemis E,Tuncel G,Asut O,Temel SG,Ergoren MC

    更新日期:2020-01-01 00:00:00

  • In vitro methods to study the interplay of drug metabolism and efflux in the intestine.

    abstract::This review provides an overview of the in vitro methods currently used in studies of intestinal drug metabolism and active efflux with a special emphasis on the efflux- metabolism interplay. These methods include e.g. expressed enzymes or efflux transporters, fractionated intestinal cells, cell lines, primary cells, ...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审

    doi:

    authors: Siissalo S,Heikkinen AT

    更新日期:2013-01-01 00:00:00

  • Safety and tolerability of agomelatine: focus on hepatotoxicity.

    abstract::Hepatotoxicity related to antidepressive pharmacotherapy is a major safety concern, particularly considering that severe forms of hepatic failure with fatal outcome have been reported. Severe hepatotoxic adverse drug reactions were also reported for agomelatine (AGM), an antidepressive agent, which was approved for th...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审

    doi:10.2174/1389200215666140926155041

    authors: Gahr M,Kratzer W,Fuchs M,Connemann BJ

    更新日期:2014-01-01 00:00:00

  • Evaluation of drug interactions with P-glycoprotein in drug discovery: in vitro assessment of the potential for drug-drug interactions with P-glycoprotein.

    abstract::The pharmacological effects of a drug are highly dependent on the absorption, metabolism, elimination, and distribution of the drug. In the past few years it has become apparent that transport proteins play a major role in regulating the distribution, elimination and metabolism of some drugs. As a consequence of our n...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审

    doi:10.2174/1389200023337559

    authors: Hochman JH,Yamazaki M,Ohe T,Lin JH

    更新日期:2002-06-01 00:00:00

  • Modulation and absorption of xenobiotics: the synergistic role of CYP450 and P-gp activities in cancer and neurodegenerative disorders.

    abstract::P-glycoprotein (P-gp) is involved in MDR and in neurodegenerative disorders such as Parkinson disease (PD), Alzheimer disease (AD) and epilepsy. Cytochrome P450 enzymes (CYP450s) catalyze the metabolism of a wide variety of endogenous and exogenous compounds including xenobiotics, drugs, environmental toxins, steroids...

    journal_title:Current drug metabolism

    pub_type: 杂志文章

    doi:10.2174/138920011798357015

    authors: Inglese C,Perrone MG,Berardi F,Perrone R,Colabufo NA

    更新日期:2011-10-01 00:00:00

  • Pharmacokinetics, Metabolism, Distribution and Permeability of Nanomedicine.

    abstract:BACKGROUND:Medical application of nanotechnology is termed as Nanomedicine and is widely used in healthcare industries. Nanotechnology has helped Physicians, Scientists and Technologists to understand the changes in cellular levels to develop nanomedicines and address the challenges faced by the healthcare sectors. Nan...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审

    doi:10.2174/1389200219666180305154119

    authors: Ravindran S,Suthar JK,Rokade R,Deshpande P,Singh P,Pratinidhi A,Khambadkhar R,Utekar S

    更新日期:2018-01-01 00:00:00

  • Stem Cells, a New Generation Model for Predictive Nano Toxicological Assessment.

    abstract::With the recent advancement in nanoscience and nanotechnology, there is a growing demand for assessment of the toxicological effects of nano materials to humans and other biological systems. And a predictive toxicology approach that uses in vitro screening assays in conjunction with in vivo study results are widely em...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审

    doi:10.2174/1389200216666151015113720

    authors: Suma RN,Mohanan PV

    更新日期:2015-01-01 00:00:00

  • N-dealkylation of arylpiperazine derivatives: disposition and metabolism of the 1-aryl-piperazines formed.

    abstract::In recent years several arylpiperazine derivatives have reached the stage of clinical application, mainly for the treatment of depression, psychosis or anxiety. Examples are the pyrimidinylpiperazine buspirone, the chlorophenylpiperazine derivatives nefazodone and trazodone, the dichlorophenylpiperazine aripiprazole a...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审

    doi:10.2174/138920007781368908

    authors: Caccia S

    更新日期:2007-08-01 00:00:00

  • The impact of in vitro binding on in vitro-in vivo extrapolations, projections of metabolic clearance and clinical drug-drug interactions.

    abstract::This review provides a vista of the current opportunities and remaining challenges in the area of in vitro-in vivo extrapolation, with particular emphasis on drug binding terms in predictive models, which has been the source of much controversy. Although the importance of fu(inc) (fraction unbound in in vitro incubati...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审

    doi:10.2174/138920006776359266

    authors: Grime K,Riley RJ

    更新日期:2006-04-01 00:00:00

  • Pharmacokinetic and metabolism determinants of fluoropyrimidines and oxaliplatin activity in treatment of colorectal patients.

    abstract::Fluoropyrimidines and oxaliplatin continued to be the mainstay of therapeutic regimens in the treatment of colorectal cancer (CRC). For this reason, pharmacokinetic and metabolism of these drugs were analyzed and the identification of accurate and validated predictive, prognostic and toxicity markers became necessary ...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审

    doi:10.2174/138920011798062300

    authors: Gnoni A,Russo A,Silvestris N,Maiello E,Vacca A,Marech I,Numico G,Paradiso A,Lorusso V,Azzariti A

    更新日期:2011-12-01 00:00:00

  • Drug-induced Cholestasis: Mechanisms, Models, and Markers.

    abstract:BACKGROUND:Drug-induced cholestasis is a risk factor in the progression of drug candidates, and poses a serious health hazard if not detected before going into a human. Intrahepatic accumulation of Bile Acids (BAs) represents a characteristic phenomenon associated with drug-induced cholestasis. METHODS:This review wil...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审

    doi:10.2174/1389200219666180427165035

    authors: Chatterjee S,Annaert P

    更新日期:2018-01-01 00:00:00

  • Active metabolites resulting from decarboxylation, reduction and ester hydrolysis of parent drugs.

    abstract::Decarboxylation, reduction and hydrolysis can yield active metabolites from the parent drug. Major therapeutic indications and metabolic routes of these drugs are reviewed. Changes in the logP values (determined and calculated) from the parent drug to the active metabolite show certain characteristics in comparison to...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审

    doi:10.2174/138920012800840437

    authors: Hartyánszky I,Kalász H,Adeghate E,Gulyás Z,Hasan MY,Tekes K,Adem A,Sótonyi P

    更新日期:2012-07-01 00:00:00

  • Review of and perspectives on the toxicology of graphene-based materials.

    abstract::Graphene possesses a wide range of potential biomedical applications because of the unique physical and chemical properties. However, the side effects of grapheme and its derivatives on a number of biological models even on human body are still not very clear. Therefore, to properly assess the potential risk of graphe...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审

    doi:10.2174/138920021131400108

    authors: Xu C,Wang J,Xu Y,Shang G,Wang R,Lin Y

    更新日期:2013-10-01 00:00:00

  • Transcriptome and proteome analyses of drug interactions with natural products.

    abstract::Advances in high-throughput technologies to measure genome-scale changes of genes, proteins, and other biomolecular components ('omics') in complex biological systems have dramatically revolutionized biomedical research. However, the benefits of utilizing omics information in drug development have not yet been fully r...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审

    doi:10.2174/138920008786927802

    authors: Fang H,Wang K,Zhang J

    更新日期:2008-12-01 00:00:00

  • Impact of various factors on pharmacokinetics of bioactive polyphenols: an overview.

    abstract::Several epidemiological studies throughout the years have suggested that polyphenols from fruits and vegetables promote health and reduce the risk of certain chronic and neurodegenerative diseases. Yet, it has been proved to be extremely difficult to quantitatively establish the benefit afforded by polyphenols, princi...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审

    doi:10.2174/1389200214666131210144115

    authors: Rubió L,Macià A,Motilva MJ

    更新日期:2014-01-01 00:00:00

  • Long Circulating Polymeric Nanoparticles for Gene/Drug Delivery.

    abstract:BACKGROUND:The prolonged circulation time of nanoparticles in the blood is a prerequisite to realize a controlled and targeted (passive or active targeting) release of the encapsulated gene/drug at the desired site of action. The most popular method to mask or camouflage nanoparticles is the adsorbed, grafted or conjug...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审

    doi:10.2174/1389200219666171207120643

    authors: Hu J,Sheng Y,Shi J,Yu B,Yu Z,Liao G

    更新日期:2018-01-01 00:00:00