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Paediatric clinical pharmacology
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
Most drugs are lipophilic and metabolised into hydrophilic compounds which are eliminated through the kidneys. Biotransformation reactions are usually classified into phase 1 and phase 2 reactions, in various combinations depending on the drug concerned.
Functions of the Liver
Published in Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal, Principles of Physiology for the Anaesthetist, 2020
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal
The liver has an important role in eliminating both endogenous and exogenous compounds. As most compounds are lipophilic or partially ionized, biotransformation in the liver converts these compounds to hydrophilic substances that may be readily eliminated either by the kidneys or in bile. The biotransformation reactions are divided into two distinct phases: phase I reactions (oxidation, reduction and hydrolysis) and phase II reactions (glucuronidation, sulphation and acetylation).
Essential Pharmacology of Abused Drugs
Published in Frank Lynn Iber, Alcohol and Drug Abuse as Encountered in Office Practice, 2020
Nearly all drugs are biotransformed, usually in the liver, to a different chemical form. In this process most drugs are rendered biologically inactive, and the new, more polar products are more readily excreted by either the kidney or liver or both. A few drugs are converted into active products by this process. Thus, codeine and heroin are both biotransformed to morphine, but at different rates; the morphine is the active form. Diazepam is metabolized to many different products, nearly half of which are biologically active. Biotransformation always converts drugs to a form that is more readily excretable by the liver or kidney. Highly lipid-soluble drugs are converted to water-soluble ones, making biliary or renal excretion much more likely; as part of this solubility change the volume of distribution is diminished.
The alteration of drug metabolism enzymes and pharmacokinetic parameters in nonalcoholic fatty liver disease: current animal models and clinical practice
Published in Drug Metabolism Reviews, 2023
Yan Zhu, Li Chen, Yuqi He, Lin Qin, Daopeng Tan, Zhaojun Bai, Yu Song, Yu-He Wang
The biotransformation processes of drugs in vivo are mainly divided into two phases, phase I and phase II drug metabolic reactions. Phase I metabolism consists of functionalization reactions, mainly involving cytochrome P450 (CYP450) enzymes. Phase II drug metabolism is a conjugation reaction that includes glucuronidation, sulfation, and glutathione coupling. The most common phase II drug metabolism enzymes (DMEs) are uridine 5′-diphospho-glucuronosyltransferases (UGTs), glutathione S-transferases (GSTs), and sulfotransferases (SULTs) (Almazroo et al. 2017). DMEs are mainly found in the liver, lung, kidney, small intestine, placenta, and skin, but the highest levels are located in the intestinal epithelial cells and the liver (Danielson 2002). In chronic liver disease states, the expression and activity of phase I and II DMEs could be altered. The alterations potentially affect the blood/plasma clearance of drugs eliminated by hepatic metabolism or biliary excretion, it can also affect plasma protein binding, which in turn could influence the processes of distribution and elimination (Verbeeck 2008).
Meeting report of the second European biotransformation workshop
Published in Xenobiotica, 2022
M. Walles, A. Pähler, E. M. Isin, L. Weidolf
Antibody–drug conjugates (ADCs) combine the high specificity of monoclonal antibodies (mAbs) and the potency of active payloads to increase efficacy and safety margins. The drugs are linked either to the side chain amino groups of lysines or to sulfhydryl groups of cysteines after controlled reduction of interchain disulphide bonds or by site-specific conjugations. It is of crucial importance to understand the biotransformation pathways. ADC biotransformation may occur either at the systemic level as well as at the targeted tissue or at the undesired tissue level which may result in loss of activity and could be responsible for safety issues. In vitro and in vivo studies are conducted at early stages of drug development. These evaluations should be accompanied with an appropriate bioanalytical strategy aiming at measuring the pharmacologically active forms of the payload derived species in circulation including the related metabolites.
Impacts of ingested MWCNT-Embedded nanocomposites in Japanese medaka (Oryzias latipes)
Published in Nanotoxicology, 2021
Melissa Chernick, Alan Kennedy, Treye Thomas, Keana C. K. Scott, Christine Ogilvie Hendren, Mark R. Wiesner, David E. Hinton
Histology also showed that exposure to materials containing MWCNTs (pristine or abraded nanocomposites) resulted in appreciable gallbladder and biliary abnormalities. MWCNTs may interfere with processes such as protein and lipid secretion and biliary transport (Shi et al. 2011). It is well-known that hepatic biotransformation is a detoxification process important for the excretion of toxic substances (Braunbeck 1998). Both hepatocytes and intrahepatic biliary epithelial cells are intimately involved (Hinton and Couch 1998). Uptake of substances at the sinusoidal surface of hepatocytes followed by their intracellular transport and later excretion into bile fluid at bile canaliculi are essential functions in detoxification (Hinton et al. 2001). Important to note were the damaged biliary epithelial cells in these treatment groups. Such alteration and dysfunction could lead to biliary retention and subsequent buildup of bile. We believe this to be consistent with the enlarged gallbladders we observed and with our common finding of biliary necrosis. It is likely that the combination of these features and actions of responding cells around them led to the damage in these fish. In the present study, only sections of fish exposed to nanocomposites showed hepatocellular alterations. It is unclear as to why exactly this response was only observed in these groups and may be indicative of a mixture effect.