Formation of potentially toxic metabolites of drugs in reactions catalyzed by human drug-metabolizing enzymes.

Data are presented on the formation of potentially toxic metabolites of drugs that are substrates of human drug metabolizing enzymes. The tabular data lists the formation of potentially toxic/reactive products. The data were obtained from in vitro experiments and showed that the oxidative reactions predominate (with 96% of the total potential toxication reactions).

Roles of selected non-P450 human oxidoreductase enzymes in protective and toxic effects of chemicals: review and compilation of reactions.

This is an overview of the metabolic reactions of drugs, natural products, physiological compounds, and other (general) chemicals catalyzed by flavin monooxygenase (FMO), monoamine oxidase (MAO), NAD(P)H quinone oxidoreductase (NQO), and molybdenum hydroxylase enzymes (aldehyde oxidase (AOX) and xanthine oxidoreductase (XOR)), including roles as substrates, inducers, and inhibitors of the enzymes. The metabolism and bioactivation of selected examples of each group (i.e.

Metabolism and interactions of Ivermectin with human cytochrome P450 enzymes and drug transporters, possible adverse and toxic effects.

The review presents metabolic properties of Ivermectin (IVM) as substrate and inhibitor of human P450 (P450, CYP) enzymes and drug transporters. IVM is metabolized, both in vivo and in vitro, by C-hydroxylation and O-demethylation reactions catalyzed by P450 3A4 as the major enzyme, with a contribution of P450 3A5 and 2C9. In samples from both in vitro and in vivo metabolism, a number of metabolites were detected and as major identified metabolites were 3″-O-demethylated, C4-methyl hydroxylated, C25 isobutyl-/isopropyl-hydroxylated, and products of oxidation reactions.

Human Family 1-4 cytochrome P450 enzymes involved in the metabolic activation of xenobiotic and physiological chemicals: an update.

This is an overview of the metabolic activation of drugs, natural products, physiological compounds, and general chemicals by the catalytic activity of cytochrome P450 enzymes belonging to Families 1-4. The data were collected from > 5152 references. The total number of data entries of reactions catalyzed by P450s Families 1-4 was 7696 of which 1121 (~ 15%) were defined as bioactivation reactions of different degrees.

Metabolism and Interactions of Chloroquine and Hydroxychloroquine with Human Cytochrome P450 Enzymes and Drug Transporters.

Background: In clinical practice, chloroquine and hydroxychloroquine are often co-administered with other drugs in the treatment of malaria, chronic inflammatory diseases, and COVID-19. Therefore, their metabolic properties and the effects on the activity of cytochrome P450 (P450, CYP) enzymes and drug transporters should be considered when developing the most efficient treatments for patients.

Methods: Scientific literature on the interactions of chloroquine and hydroxychloroquine with human P450 enzymes and drug transporters, was searched using PUBMED.

Human cytochrome P450 enzymes 5-51 as targets of drugs and natural and environmental compounds: mechanisms, induction, and inhibition - toxic effects and benefits.

Cytochrome P450 (P450, CYP) enzymes have long been of interest due to their roles in the metabolism of drugs, pesticides, pro-carcinogens, and other xenobiotic chemicals. They have also been of interest due to their very critical roles in the biosynthesis and metabolism of steroids, vitamins, and certain eicosanoids. This review covers the 22 (of the total of 57) human P450s in Families 5-51 and their substrate selectivity.

Development and Uses of Offline and Web-Searchable Metabolism Databases - The Case of Benzo[a]pyrene.

Background: The present work describes development of offline and web-searchable metabolism databases for drugs, other chemicals, and physiological compounds using human and model species, prompted by the large amount of data published after year 1990. The intent was to provide a rapid and accurate approach to published data to be applied both in science and to assist therapy.

Methods: Searches for the data were done using the Pub Med database, accessing the Medline database of references and abstracts.

Survey of Human Oxidoreductases and Cytochrome P450 Enzymes Involved in the Metabolism of Xenobiotic and Natural Chemicals.

Analyzing the literature resources used in our previous reports, we calculated the fractions of the oxidoreductase enzymes FMO (microsomal flavin-containing monooxygenase), AKR (aldo-keto reductase), MAO (monoamine oxidase), and cytochrome P450 participating in metabolic reactions. The calculations show that the fractions of P450s involved in the metabolism of all chemicals (general chemicals, natural, and physiological compounds, and drugs) are rather consistent in the findings that >90% of enzymatic reactions are catalyzed by P450s. Regarding drug metabolism, three-fourths of the human P450 reactions can be accounted for by a set of five P450s: 1A2, 2C9, 2C19, 2D6, and 3A4, and the largest fraction of the P450 reactions is catalyzed by P450 3A enzymes.

Summary of information on the effects of ionizing and non-ionizing radiation on cytochrome P450 and other drug metabolizing enzymes and transporters.

The present paper is an update of data on the effects of ionizing radiation (γ-rays, X-rays, high energy UV, fast neutron) caused by environmental pollution or clinical treatments and the effects of non-ionizing radiation (low energy UV) on the expression and/or activity of drug metabolism (e.g., cytochrome P450 (CYP), glutathione transferase (GST)), enzymes involved in oxidative stress (e.

Contributions of human enzymes in carcinogen metabolism.

Considerable support exists for the roles of metabolism in modulating the carcinogenic properties of chemicals. In particular, many of these compounds are pro-carcinogens that require activation to electrophilic forms to exert genotoxic effects. We systematically analyzed the existing literature on the metabolism of carcinogens by human enzymes, which has been developed largely in the past 25 years.

Update information on drug metabolism systems--2009, part I.

The field of drug metabolism has changed dramatically in the past generation. Two of the driving forces are the advances in analytical chemistry and our understanding of the biological systems. With regard to the former, the advances in liquid chromatography-mass spectrometry (LC-MS) are extremely impressive, and the speed of analysis has been increased even more with the recent developments in ultraperformance LC (UPLC).

Update information on drug metabolism systems--2009, part II: summary of information on the effects of diseases and environmental factors on human cytochrome P450 (CYP) enzymes and transporters.

The present paper is an update of the data on the effects of diseases and environmental factors on the expression and/or activity of human cytochrome P450 (CYP) enzymes and transporters. The data are presented in tabular form (Tables 1 and 2) and are a continuation of previously published summaries on the effects of drugs and other chemicals on CYP enzymes (Rendic, S.; Di Carlo, F.

Strategies for more effective and reliable ADME. 30-31 March 2004, London, UK.

This conference was organised by Vision in Business, in order to address the issue that 'more than 40% of drug preclinical failure is due to ADME-related issues and many drugs are later withdrawn because of unanticipated drug-drug interactions (C Masimirembwa, AstraZeneca Mölndal, Sweden). Academic and industrial scientists were brought together to discuss and present current knowledge/theories on subjects of importance in preclinical and clinical drug development. These included in vivo/in vitro correlations, approaches and experimental models used, in silico models and methods, metabolic databases and their application, as well as safety and financial outcomes.

Summary of information on human CYP enzymes: human P450 metabolism data.

This chapter is an update of the data on substrates, reactions, inducers, and inhibitors of human CYP enzymes published previously by Rendic and DiCarlo (1), now covering selection of the literature through 2001 in the reference section. The data are presented in a tabular form (Table 1) to provide a framework for predicting and interpreting the new P450 metabolic data. The data are formatted in an Excel format as most suitable for off-line searching and management of the Web-database.

Metabolism of anabolic steroids by recombinant human cytochrome P450 enzymes. Gas chromatographic-mass spectrometric determination of metabolites.

Metabolism of steroid hormones with anabolic properties was studied in vitro using human recombinant CYP3A4, CYP2C9 and 2B6 enzymes. The enzyme formats used for CYP3A4 and CYP2C9 were insect cell microsomes expressing human CYP enzymes and purified recombinant human CYP enzymes in a reconstituted system. CYP3A4 enzyme formats incubated with anabolic steroids, testosterone, 17alpha-methyltestosterone, metandienone, boldenone and 4-chloro-1,2-dehydro-17alpha-methyltestosterone, produced 6beta-hydroxyl metabolites identified as trimethylsilyl (TMS)-ethers by a gas chromatography-mass spectrometry (GC-MS) method.

Drug interactions of H2-receptor antagonists involving cytochrome P450 (CYPs) enzymes: from the laboratory to the clinic.

This paper reviews the main steps in the research of the interactions of H2-receptor antagonist drugs with cytochrome P450 (CYP) enzymes. Cimetidine, ranitidine, and related compounds are used as examples. The results from in vitro studies are related to the observed clinically significant in vivo drug-drug and drug-chemical interactions.

Binding of (+)- and (-)-isomers and racemate of etomoxir to human serum albumin and effect of stearic acid and stanozolol.

Binding of (+)- and (-)-isomers and the racemate of sodium 2[6-(4-chlorophenoxy)-hexyl]-oxiran-2-carboxylate dihydrat (etomoxir) to the human serum albumin (HSA) was studied by the gel filtration method. The experimental results are presented graphically using the method of Scatchard. Measurements revealed the following data on the binding: (a) for either of the isomers there are two independent and nonequivalent classes of binding sites on the HSA molecule; (b) the binding constants calculated for both isomers were of the same order of magnitude (K1/n approximately 20 x 10(5) L.

Urinary excretion and metabolism of orally administered mefenorex.

Metabolic pathways and the pharmacokinetic profile of mefenorex ((+/-)N-(3-chloropropyl)-1-methyl-2-phenylethylamine), and its main metabolite amphetamine (1-methyl-2-phenylethylamine) have been studied in two healthy volunteers, after a single oral dose of mefenorex (1.2 mg/kg body weight for a male subject and 2.4 mg/kg body weight for a female subject).

Biotransformations and plasma-level curves of chiral 1,4-benzodiazepine-2-ones.

Biotransformations of chiral 1,4-benzodiazepine-2-ones, (S)- and (R)-1 (7-chloro-1,3-dihydro-3 (S and R)-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one) in untreated and phenobarbital-pretreated rats were investigated. In urine, a 4'-oxygenated metabolite (compound 2) was identified as the biotransformation product from both enantiomers, (S)-2 being present in much higher amounts than (R)-2. Unchanged parent compounds were not found in urine.