Gastrointestinal Function and Toxicology in Canines
Shayne C. Gad in Toxicology of the Gastrointestinal Tract, 2018
Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems [29–34,123,136,148,202,230,236,263,273,286,296,301,316,364,410]. More generally, xenobiotic metabolism (from the Greek xenos, “stranger” and biotic, “related to living beings”) is the set of metabolic pathways that modify the chemical structure of xenobiotics, which are compounds foreign to an organism’s normal biochemistry, such any drug or poison. These pathways are a form of biotransformation present in all major groups of organisms and are considered to be of ancient origin. These reactions often act to detoxify poisonous compounds (although in some cases the intermediates in xenobiotic metabolism can themselves cause toxic effects). The study of drug metabolism is called pharmacokinetics.
The Effects of Experimental Diabetes on the Cytochrome P450 System and Other Metabolic Pathways
John H. McNeill in Experimental Models of Diabetes, 2018
Failure to appreciate quantitative as well as qualitative changes, i.e., altered isoform profiles, may lead to two adverse situations, especially when the drugs concerned are characterized by a narrow therapeutic index. On the one hand, increased metabolic capacity will mean lower plasma levels that rapidly decrease; the consequence is a less-intense and shorter pharmacological effect than envisaged. In extreme cases, the effect may be totally abolished. On the other hand, suppression of drug-metabolizing activity will lead to higher plasma drug levels and, on repeated administration, the drug will accumulate with the possible appearance of adverse affects normally associated with overdosage. Clearly, an understanding of the effects of disease on drug metabolism is essential, in that it will allow appropriate precautions to be taken to alter the dose regimen to ensure that the desirable effect is maintained and the likelihood of toxicity is minimized. Alternatively, it may be possible to select other drugs where metabolism is catalyzed by enzyme systems whose activity is not influenced by the disease.
Improving knowledge and safety: pharmacological principles
Sherri Ogston-Tuck in Introducing Medicines Management, 2013
For many drugs, however, there are two phases of drug metabolism. Both of which are complex and require a deep knowledge of chemistry, which is beyond the scope of this book. Suffice here to say that phase one involves three reactions referred to as oxidation, reduction and hydrolysis; and phase two involves conjugation reactions, where the aim is to make the molecule more lipophobic (that is, less lipid soluble) and reduce the possibility of reabsorption in the renal tubules. Drug metabolism can result in the activation or deactivation of the chemical. Enzymes in the liver are responsible for modifying the biochemical composition of drugs and their action is often referred to as xenobiotic metabolism. Most drugs, therefore are ‘xenobiotics’ or what may be commonly referred to as organic chemicals (Trounce, 2000).
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).
Comprehensive identification, fragmentation pattern, and metabolic pathways of gefitinib metabolites via UHPLC-Q-TOF-MS/MS: in vivo study of rat plasma, urine, bile, and faeces
Published in Xenobiotica, 2021
Xun Gao, Yue Zhang, Tiantian Feng, Lei Cao, Wenjing Wu, Kunming Qin
Drug metabolism can be defined as the enzyme-catalysed conversion of a drug into chemically distinct products (metabolites). The main function of drug metabolism is detoxification, which maximises the benefits and minimises the side-effects (Pirmohamed 2008, Zhang and Tang 2018). Currently, the in vitro metabolism of GEF has been extensively investigated. Mckillop et al. have identified 16 metabolites of gefitinib in human liver microsomes in vitro (Mckillop et al. 2004b). Liu et al. have identified 34 GEF metabolites in human and mouse liver microsomes (in vitro) (Liu et al. 2015). Alhoshani et al. have focussed on one cyanide and two methoxylamine-adducts reactive metabolites in the rat heart microsomes (in vitro) (Alhoshani et al. 2020). For the in vivo study, Mckillop et al. have described only 9 metabolites in rat, dog and human (Mckillop et al. 2004a), 7 of them were identical to the metabolites identified in this study. Therefore, the study of metabolites and metabolic pathways of GEF in vivo is vital for rational drug use of GEF. In addition, the study of metabolites can lead candidates during lead optimisation. Compared with the parent compound, there is great potential in developing an active metabolite as a drug in terms of improved pharmacodynamics, pharmacokinetics and safety (Fura 2006).
Establishment and assessment of a novel in vitro bio-PK/PD system in predicting the in vivo pharmacokinetics and pharmacodynamics of cyclophosphamide
Published in Xenobiotica, 2018
Shanshan Tong, Hong Sun, Caifu Xue, Hanmei Chen, Jing Liu, Huiying Yang, Ning Zhou, Xiaoqiang Xiang, Weimin Cai
Drug metabolism is a very important in vivo process that is closely related to the pharmacological and toxicological effects of the drug. However, the majority of commonly used in vitro models to study PDs neglect the influence of metabolism. This leads to a poor correlation between in vivo and in vitro data. More often, the effects of metabolism on drug efficacy require in vivo experiments. However, the in vivo experiments are usually time- and labor-consuming. Furthermore, the drug doses of in vivo experiments are larger than the in vitro experiments which indicates that the cost is considerable especially for those expensive drugs. Moreover, it is encouraged to reduce the use of animals from the perspective of animal welfare. With the expansion of compound libraries, it is of practical and scientific significance to evaluate and predict the real PK parameters and PD process before in vivo studies. At present, there are no conventional in vitro methods that can simulate in vivo metabolic and pharmacological processes with a high level of convenience and effectiveness.
Related Knowledge Centers
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