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Model-Informed Drug Development
Published in Wei Zhang, Fangrong Yan, Feng Chen, Shein-Chung Chow, Advanced Statistics in Regulatory Critical Clinical Initiatives, 2022
Clearance is generally used to quantify elimination rates in liver, kidney, or other organs. At the body level, total plasma clearance (CLtot) describes the sum of multiple clearance processes that occur simultaneously within multiple organs. Here, CLtot is the apparent rate at which a compound is removed from the systemic circulation. In PB-PK modeling, the relative contribution of each organ to CLtot can be further differentiated by quantifying the specific elimination rate in each organ.
Gold Nanomaterials at Work in Biomedicine *
Published in Valerio Voliani, Nanomaterials and Neoplasms, 2021
Xuan Yang, Miaoxin Yang, Pang Bo, Madeline Vara, Younan Xia
As recommended by the US Food and Drug Administration (FDA), pharmaceutical drugs should be eliminated via metabolism or excretion processes within a reasonable period of time in order to reduce accumulation and potential side effects. To meet this requirement, the mechanism of clearance for Au nanoparticles has been an active subject of research [613]. Two aspects of clearance need to be addressed separately: the clearance from the bloodstream and from the body, respectively. Clearance from the blood pool is more frequently studied as it determines the efficacy of lesion targeting and the removal via different mechanisms, in conjunction with the pharmacokinetics and biodistribution studies discussed above [613]. The blood clearance property will directly impact the effectiveness of a nanomaterial-based medicine and its toxicity. On the other hand, clearance from the body addresses the amount of nanomaterials eliminated from the body by urine and bile while either during clearance or after they have been cleared from the blood pool. In this review, we call the removal of nanoparticles from body by hepatic cells biliary clearance to differentiate it from the blood clearance process. The elimination of Au nanomaterials from the body is less well studied as Au cannot be digested by enzymes within the body [739, 740]. This is one of the major barriers that limits the clinical use of most Au-based agents. To make Au nanomaterials clearable, we need a better understanding of the details involved in both renal and biliary clearance.
The Structural Biology, Biochemistry, Toxicology, and Military Use of the Ricin Toxin and the Associated Treatments and Medical Countermeasures for Ricin Exposure
Published in Brian J. Lukey, James A. Romano, Salem Harry, Chemical Warfare Agents, 2019
Terry J. Henderson, George Emmett, Russell M. Dorsey, Charles B. Millard, Ross D. LeClaire, Harry Salem
Clearance from the respiratory tract is the physical removal of insoluble and poorly soluble particles as well as the dissolution and absorption of soluble particles (McClellan and Henderson, 1995; Phalen, 2009; Schlesinger, 1985). Particle deposition is the critical first step in determining the subsequent clearance processes. The respiratory tract can be divided into three unique regions based on clearance mechanisms. Inhaled particles deposited in the posterior nares (region 1) can become caught up in mucus and transported by mucociliary action through the nasopharynx and into the gastrointestinal (GI) tract (Stuart, 1984); other mechanisms that can also become involved include sneezing, coughing, swallowing, and nose blowing. Particles reaching the larynx and passing through successive generations of conducting airways to the terminal bronchioles (region 2) can also be deposited on mucus that is propelled upward by underlying cilia for clearance to the GI tract. Finally, inhaled insoluble particles that are deposited below the ciliated epithelium, on the surfaces of the respiratory bronchioles, alveolar ducts, alveolar sacs, and alveoli (region 3), will be cleared more slowly to the GI tract or will remain with only gradual dissolution or removal following phagocytosis by pulmonary macrophages. Soluble particles can be absorbed directly into blood or lymphatic channels after dissolution in respiratory fluids.
Understanding the role of chronopharmacology for drug optimization: what do we know?
Published in Expert Review of Clinical Pharmacology, 2023
Akio Fujimura, Kentaro Ushijima
The main determinants of metabolism for drugs with a low intrinsic clearance (capacity-limited drugs) are liver enzyme activity and plasma protein binding. The mRNA expression levels of drug-metabolizing enzymes in the liver are reported to show circadian variation [28]. Cytochrome P450 3A (CYP3A) is a hepatic drug-metabolizing enzyme that is involved in the metabolism of many medications. Ohno et al. collected human urine samples at 9:00–13:00, 13:00–17:00, 17:00–21:00, and 21:00–9:00 and measured hepatic CYP3A activity according to the urinary 6-beta-hydroxycortisol to cortisol ratio [29]. They observed circadian changes in this ratio, with the peak occurring between 17:00 and 21:00. Therefore, CYP3A-mediated hepatic metabolism of capacity-limited drugs, such as warfarin and phenytoin, might be greater during the early evening (17:00–21:00) than at any other time of the day in humans.
Drug metabolic stability in early drug discovery to develop potential lead compounds
Published in Drug Metabolism Reviews, 2021
Siva Nageswara Rao Gajula, Nimisha Nadimpalli, Rajesh Sonti
Predicting in vivo pharmacokinetic data from the in vitro drug metabolism data is of great interest in preclinical studies. Data acquired from the in vitro metabolism helps in selecting potent leads for further development. Knowledge of drug clearance provides information about the dose required to maintain steady-state plasma concentration and drug disposition description (Chiou 1982; Bardal et al. 2011). Clearance is the volume of plasma from which the drug is removed per unit of time (Chiou 1982; Bardal et al. 2011). Plasma clearance (or total systemic clearance) can be characterized by all the metabolizing and eliminating organs involved in the drug clearance (Wilkinson and Shand 1975; Dowd 2017). These organs primarily include the liver (hepatic clearance) and kidney (renal clearance). Hepatic clearance is the liver's ability to remove the drug from the blood and is related to two variables: hepatic blood flow rate and intrinsic hepatic clearance (Wilkinson and Shand 1975). On the other hand, renal clearance is the volume of blood or plasma completely cleared off the drug by the kidneys per unit time (Tucker 1981).
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).