Toxicokinetics
Frank A. Barile in Barile’s Clinical Toxicology, 2019
Biotransformation refers to the alteration of a chemical (xenobiotic) in biological systems.* Xenobiotic transformation plays a crucial role in maintaining homeostasis during chemical exposure. This is accomplished by converting lipid-soluble (nonpolar), nonexcretable xenobiotics to polar, water-soluble compounds accessible for elimination in the bile and urine. Thus, the major desirable outcomes of biotransformation include facilitation of renal excretion; conversion of toxic parent compounds to nontoxic metabolites (i.e., detoxification); conversion of nontoxic parent compounds to toxic metabolites (i.e., bioactivation); and conversion of nonreactive compounds to reactive metabolites (pharmacological bioactivation). The catalysts for xenobiotic transformation are incorporated into Phase I and Phase II enzyme reactions. Although occurring primarily in the liver, other organs, such as kidney, lung, and dermal tissue, have large capacities for these reactions. Table 10.9 outlines the major differences between Phase I and Phase II reactions, which will be discussed in detail in the following subsections.
Introduction
Francis L. S. Tse, James M. Jaffe in Preclinical Drug Disposition, 2017
Metabolism (biotransformation) is the process by which the administered compound is structurally and/or chemically changed in the body by either enzymatic or nonenzymatic reactions. The path-ways by which this occurs are classified as either phase I or phase II reactions. Phase I processes convert the compound by oxidation, reduction, or hydrolysis while phase II, often termed conjugation reactions, involves coupling between the compound or its metabolite and endogenous sub-strate, especially glucuronic or sulfuric acid. Although these reactions can take place in various tissues and organs throughout the body, compounds are predominantly metabolized in the liver by microsomal enzymes located in the endoplasmic reticulum. Normally, metabolism results in a molecule that is substantially less active than the parent compound, although in some phase I reactions, the metabolite may be more active than the parent molecule (prodrug). Also, since metabolites are generally more polar than the original compound, their volumes of distribution are reduced and their ability to be eliminated via the kidneys is greatly increased.
Paediatric clinical pharmacology
Evelyne Jacqz-Aigrain, Imti Choonara in Paediatric Clinical Pharmacology, 2021
Clinicians recognise that not all patients respond similarly to the same medication, even when doses are normalised for body weight or surface area. This may be attributed to lack of compliance with the therapeutic regimen, but the main reason is the existence of pharmacokinetic differences between individuals. Individual variations in drug biotransformation may result from genetic factors, age, concomitant drug therapy, other environmental factors (foods, toxins, etc.) and disease. Genetically determined cytochrome P450 polymorphism can cause several-fold differences in the metabolic rate between rapid and slow metabolisers [1]. Some conjugation pathways, such as glucuronidation, are reduced in the newborn and accumulation of chloramphenicol was associated with the “grey baby syndrome” [2]. Elevated serum concentrations of theophylline are seen when administered concomitantly with erythromycin, which interferes with cytochrome P450-mediated metabolism [3]. Ciclosporin blood concentrations increase by concurrent administration of grapefruit juice, a CYP3A4 inhibitor [4]. Children with cystic fibrosis or burns have more rapid clearance of several drugs as compared with unaffected individuals [5,6].
Mechanistic studies on the drug metabolism and toxicity originating from cytochromes P450
Published in Drug Metabolism Reviews, 2020
Chaitanya K. Jaladanki, Anuj Gahlawat, Gajanan Rathod, Hardeep Sandhu, Kousar Jahan, Prasad V. Bharatam
Drug metabolism is one of the discrete pharmacokinetic processes, which converts lipophilic centers to hydrophilic centers during drug biotransformation. This is to facilitate the excretion of drugs from the body in a safe manner. Biotransformation is the metabolic breakdown of the drugs/xenobiotics via specialized enzymatic systems (e.g. CYP450 family) (De Groot 2006). It is a crucial process because, the lipophilic nature of the drugs allows them to stay longer in the body, which may in turn leads to toxicity. Figure 1 shows the known generalized pathways associated with drug metabolism (Caira and Ionescu 2006). Metabolism primarily occurs in liver (Remmer 1970) but other organs are also involved – kidney, placenta, adrenal gland, gastrointestinal tract (GIT) and the skin. The cytochromes that are mainly involved in drug metabolism are Cytochrome P450 (CYP450) 1A1, CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, among them, CYP3A4 is responsible for the metabolism of ∼50% of the drugs (Sheweita 2000).
Subcutaneous catabolism of peptide therapeutics: bioanalytical approaches and ADME considerations
Published in Xenobiotica, 2022
Simone Esposito, Laura Orsatti, Vincenzo Pucci
The most relevant biotransformation occurring at the SC injection site is the cleavage of peptide bonds by means of proteases or peptidases, which generates smaller peptides or amino acids. This type of biotransformation is referred to as catabolism, in contrast to the term metabolism used for biotransformation mainly observed in small molecules. Proteolytic enzymes are broadly divided into two categories: exopeptidases, which catalyse the cleavage at the N-terminal or C-terminal removing a single amino acid, and endopeptidases, which cleave peptide bonds within the sequence (López-Otín and Bond 2008). Exopeptidases are intuitively divided into aminopeptidases and carboxypeptidases, while endopeptidases are traditionally classified on the basis of their catalytic site as cysteine peptidases (e.g. dipeptidyl peptidase IV), aspartic peptidases (e.g. pepsin), serine peptidases (e.g. cathepsin B), and metallopeptidases (e.g. matrix metalloprotease 2 and 9) (de Veer et al. 2014a).
Modulation of xenobiotic metabolizing enzyme activities in rat liver by co-administration of morin, endosulfan, and 7,12-dimethylbenz[a]anthracene
Published in Drug and Chemical Toxicology, 2020
Canan Sapmaz, Tulin Firat, Aysel Kukner, Azra Bozcaarmutlu
Within the body, xenobiotics are metabolized by xenobiotic metabolizing enzymes. The biotransformation reactions catalyzed by these enzymes are broadly divided into Phase I and phase II reactions. Oxidative phase I reactions are mainly catalyzed by CYP dependent monooxygenases. The CYPs are a superfamily of proteins involved in oxidative metabolism of both endogenous (steroids, fatty acids, prostaglandins, biogenic amines, and retinoids) and exogenous compounds (drugs, alcohols, organic solvents, anesthetic agents, dyes, environmental pollutants, and chemicals) (Gonzalez 1988, Arinç and Bozcaarmutlu 2003, Hodgson and Rose 2007, Zanger and Schwab 2013). Phase II biotransformation reactions are conjugation reactions in the xenobiotic metabolism. Glutathione S-transferases (GSTs) are a group of enzymes involved in the conjugation reactions of xenobiotics. They catalyze the conjugation of phase I metabolites, environmental carcinogens, and epoxide intermediates with reduced glutathione (GSH) (Gallagher et al. 1996, Wu and Dong 2012). During metabolic reactions, ROS are produced and these highly reactive molecules may interact with DNA or the other macromolecules present in the cell. Antioxidant enzymes, including catalase, superoxide dismutase, glutathione reductase (GR), and glutathione peroxidase, neutralize the toxic effects of ROS and metals (Halliwell 1995, Rahman et al. 2012). GR catalyzes the reduction of glutathione disulfide (GSSG) to GSH, and GSH contributes to the removal of reactive electrophiles through conjugation and scavenging of ROS (Carlberg and Mannervik 1985, Deponte 2013).
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