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Biotransformation of Xenobiotics in Living Systems—Metabolism of Drugs: Partnership of Liver and Gut Microflora
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
The study of drug metabolism or biotransformation is particularly important to our understanding of the time course of drugs in the body, the structuring of dosage regimens, the pharmacology and toxicology of drug metabolites, and the interactions of multivalent drug combinations (Bachmann, 2009). Since it has become evident that all patients are unique in terms of disparate therapeutic response to drugs due to differences in age, sex, genetic inheritance, coexisting disorders (particularly chronic liver disorders and advanced heart failure), concomitant therapy, and other physiological factors, monitoring individual pharmacokinetic and pharmacodynamic response will be the challenge of modern pharmacotherapy (Ahmed et al., 2016). Drug discovery requires the characterization of the enzymes involved in the metabolism of a new compound and the determination of its biotransformation pathways and metabolic stability (Foti and Dalvie, 2016). Potential impacts of species differences in drug metabolism and the potential coverage of major human metabolites in animals should be thoroughly evaluated in drug design process. Therefore, the identification of circulating metabolites in clinical trials is highly recommended as early as possible (Zhang and Tang, 2018). The more-in-depth understanding of drug metabolism in combination with modern diagnostic techniques including genomics and proteomics could yield the revolution in individual therapy (Murphy, 2001).
Pharmaceuticals: Some General Aspects
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
The term “drug” is used here in connection with recombinant therapeutic proteins (for the world market of therapeutic proteins, see Research and Markets, 2016) as well as chemically synthesized small molecules that have been approved for the treatment and prevention of diseases. Not included are diagnostic imaging agents as, e.g., Netspot (detection of rare neuroendocrine tumors) or Axumin (detection of recurrent prostate cancer) both approved by the FDA in 2016, and other compounds used for diagnostic purposes. The targets of small molecule drugs are proteins to which they bind to exert therapeutic efficacy; enzymes involved in drug metabolism are not defined here as drug target. The WHO Collaborating Centre for Drug Statistics Methodology classifies drugs by The Anatomical Therapeutic Chemical (ATC) Classification System (ATC and ATCvet) with respect to the organ or system, on which they act, their therapeutic, pharmacological, and chemical properties, etc., including, e.g., defined daily drug doses (WHOATC 2018).
Pharmacokinetic analysis
Published in Ronald L. Fournier, Basic Transport Phenomena in Biomedical Engineering, 2017
Once the drug is absorbed and distributed throughout the body, a variety of biochemical reactions will begin to degrade the drug. This breakdown of the drug is part of the body’s natural defense against foreign materials. Metabolism of the drug is beneficial in the sense that it limits the time of drug action and, in some cases, it produces the active form of the drug. These biochemical reactions, driven by existing enzymes, occur in a variety of organs and tissues. However, the major site of drug metabolism is within the liver, and other important sites include the kidneys, lungs, blood, and the GI wall. The enzymatic destruction of the drug reduces its pharmacological activity because the active site related to the drug’s molecular structure is destroyed. Also, the metabolites that result tend to have increased water solubility that decreases their capillary permeability and enhances their removal from the body via the kidneys.
MOLECULAR DOCKING INVESTIGATION AND PHARMACOKINETIC PROPERTIES PREDICTION OF SOME ANILINOPYRIMIDINES ANALOGUES AS EGFR T790M TYROSINE KINASE INHIBITORS
Published in Egyptian Journal of Basic and Applied Sciences, 2021
Muhammad Tukur Ibrahim, Adamu Uzairu, Gideon Adamu Shallangwa, Sani Uba
All the reported compounds have absorbance value between 76.641 and 94.419% as the values passed the minimum recommended values of 30% which indicates good human intestinal absorption. The minimum recommended values for the blood–brain barrier (BBB) and central nervous system permeability is > 0.3 to < −1 Log BB and > −2 to < −3 Log PS, respectively. As for these compounds, Log BB is > −1 for all which implies that the compounds are better distributed to brain and Log PS for all is > −2, which are considered to penetrate the central nervous system. The enzymatic metabolism of drugs shows the biotransformation of a drug in the body. It is, therefore, very important to put into consideration the metabolism of drugs, as such the cytochrome P450 plays an important role in drug metabolism. CYP families involved in drug metabolism were 1A2, 2C9, 2C19, 2D6, and 3A4, respectively. The most important among the mention CYP families is 3A4 which all the reported compounds were found to be substrate and inhibitors of it. Total clearance is an indicator, which describes the relationship between the rate of elimination of the drug and its concentration in the body. The reported compounds showed high value of total clearance but within the accepted limit of a drug molecule in the body. Furthermore, all the reported compounds were found to be nontoxic. The overall ADMET properties of these compounds indicate their good pharmacokinetic profiles (Table 2).
Thymol Reduces Hepatorenal Oxidative Stress, Inflammation and Caspase-3#xd; Activation in Rats Exposed to Indomethacin
Published in Egyptian Journal of Basic and Applied Sciences, 2022
Tijani Abiola Stephanie, Olori O. David, Ebenezer O. Farombi
The liver and kidney are very critical organs in drug metabolism [6]. Liver is the main organ for drug metabolism, detoxifies and eliminates by-products from body and the kidney is responsible mainly for excretion, maintenance of body homeostasis and also aid in drug metabolism. These roles expose these organs to toxic assaults and injuries through oxidative stress, the discharge of pro-inflammatory markers including TNF-α and IL-1β and stimulation of apoptotic process [7]. Several proteomic and genetic biomarkers formed during hepatorenal toxicities including transaminases, alkaline phosphatase, bilirubin, cholesterol, creatinine, triglycerides, urea and uric acid level indicates the severity of hepatorenal damage [8,9].