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Paediatric clinical pharmacology
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
The major site of drug metabolism is within the liver. The gastrointestinal tract, blood cells and other organs are also involved in drug metabolism. The biological purpose of drug metabolism is to convert lipophilic (fat soluble) compounds into more polar and thus more water soluble substances that are more readily excreted into bile or urine. The enzymes involved in drug metabolism are not only involved in the breakdown of medicines but also the numerous other chemicals that humans ingest or inhale either deliberately or unwittingly.
Drug Design, Synthesis, and Development
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
In order to enter the blood stream, the drug must pass the cells lining the intestine. Once the drug has traversed the cell membranes, it can readily enter capillaries through pores that exist between the cells of the blood vessels. Upon entering the capillaries, the drug is on route to the liver, which contains enzymes designed to intercept and modify foreign chemicals in order to make them easier to excrete. This process is known as drug metabolism. This introduces the necessity for an orally active drug to be metabolically stable as well as resistant to the enzymes and hydrochloric acid of the GIT, and this presents a challenge to medicinal chemists designing new drugs.
Conversion of Natural Products from Renewable Resources in Pharmaceuticals by Cytochromes P450
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Giovanna Di Nardo, Gianfranco Gilardi
Cytochromes P450 are a large superfamily of heme-containing monoxygenases mainly acting as hydroxylases. The large number of members of this superfamily, their wide distribution in nature, and their ability to carry out different oxidation reactions on thousands of substrates make these enzymes highly interesting in the field of biocatalysis. Moreover, the physiological role of these enzymes in different organisms such as bacteria, fungi, and plants is the synthesis of natural compounds that have been used themselves as drugs or as molecular leads for the development of other active compounds. In mammals, cytochromes P450 physiologically act as the main enzymes involved in Phase-I drug metabolism as well as pro-drug activation. Thus, nature has already provided a panel of enzymes suitable to modify many molecules with different molecular scaffolds and biological activities. The knowledge on this enzymatic pool is continuously growing thanks to the progresses in genome sequencing of different organisms that provides new P450 gene sequences, new substrates and reaction carried out.
DEC1 negatively regulates CYP2B6 expression by binding to the CYP2B6 promoter region ascribed to IL-6-induced downregulation of CYP2B6 expression in HeLa cells
Published in Xenobiotica, 2021
Xiaofei Luan, Yi Zhao, Na Bu, Yue Chen, Nan Chen
An increasing number of studies have shown that the expression and activity of drug metabolising enzymes are important factors affecting individual differences in pharmacokinetics (Wilkinson 1996; Shimizu 2009). The cytochrome P450 superfamily (CYPs) represents the main enzymes responsible for phase-I drug metabolism or the light reaction of drugs. Most anticancer drugs are metabolised by CYPs and some drugs, such as podophyllotoxin, paclitaxel, vinblastine, and tamoxifen, are detoxified by CYP metabolism. Other drugs such as cyclophosphamide are activated by CYP metabolism (Evans and Relling 2004). Presently, at least 74 members of the P450 superfamily have been shown as closely related to drug metabolism. Most anticancer drugs are mainly metabolised by CYP3A, CYP2C, CYP2B, and CYP1A (Efferth and Volm 2005). Studies show that more than 95% of the metabolites of drugs and other exogenous compounds are metabolised by CYPs (Hafner et al. 2011) Therefore, studying the expression and activity of CYPs in clinical efficacy, toxicity, and antitumor effects of drugs is of great importance.
Association of polymorphism of CYP3A4, ABCB1, ABCC2, ABCG2, NFKB1, POR, and PXR with the concentration of cyclosporin A in allogeneic haematopoietic stem cell transplantation recipients
Published in Xenobiotica, 2021
Linlin Wang, Guangting Zeng, Jianqiang Li, Jia Luo, Huilan Li, Zanling Zhang
Genetic factors play an important role in drug metabolism. CsA is mainly metabolized by the cytochrome P450 (CYP) enzymes CYP3A4 and CYP3A5 mainly in the liver and is also a substrate of the P-glycoprotein (encoded by the ABCB1 gene) (Zhang et al.2013), which is involved in the absorption and elimination of CsA. Furthermore, several studies have also identified the effect of other genetic polymorphisms in ABCC2, nuclear factor-KB1(NFKB1), Cytochrome P450 oxidoreductase (POR), and pregnane X receptor (PXR) on CsA pharmacokinetics (Hesselink et al.2008, , Zhang et al.2013, Elens et al.2014, Lunde et al.2014, Sun et al.2017), but some of the results are controversial. The dose-adjusted trough concentration (Cssmin/D) not trough concentration (Cssmin) is usually used to examine the effect of these genes because the dose of CsA is always adjusted according to the ideal Cssmin. The bioavailability of CsA ranges from less than 5% to 89% in transplant patients (Hesselink et al.2008, Zhang et al.2013, Elens et al.2014, Lunde et al.2014, Sun et al.2017), which is influenced by lots of factors, including food intake, bile flow, and gastrointestinal state such as motility and length of the small intestine and diarrhea (Atiq et al.2018). These factors may mask the effect of genetic factors on CsA when CsA is given orally. Analysing the influence of these genes on the Cssmin/D of CsA seems inaccurate, without considering the administration route. As a result, many of these conclusions are controversial.
Comprehensive metabolism study of swertiamarin in rats using ultra high-performance liquid chromatography coupled with Quadrupole-Exactive Orbitrap mass spectrometry
Published in Xenobiotica, 2021
Beibei Ma, Tianyu Lou, Tingting Wang, Ruiji Li, Jinhui Liu, Shangyue Yu, Yudong Guo, Zhibin Wang, Jing Wang
Drug metabolism refers to the process in which the chemical structure of a drug alters beneath the action of numerous drug metabolic enzymes in the body (Hua et al.2019), also known as biotransformation. Since human beings began to use drugs to treat diseases, the metabolic process of drugs had been the focus of drug research. Lack of understanding of the in vivo metabolism of drugs may lead to treatment failure, increased side effects and even death. Therefore, drug metabolism is considered to be one of the most critical factors affecting drug efficacy. However, the previous studies on the metabolism of drug components tended to focus on the metabolic reactions directly related to the parent drug, but ignored the metabolic process of some intermediates, coupled with the complexity of the human metabolic system, some minor metabolites were difficult to detect. For example, in the metabolic studies related to swertiamarin, only a small number of metabolites including ECR had been found, which were far from sufficient for elucidating the pharmacological mechanism and further development of swertiamarin (Wang et al.2014, Wu et al.2015b).