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Nonclinical Studies
Published in John M. Centanni, Michael J. Roy, Biotechnology Operations, 2016
John M. Centanni, Michael J. Roy
Clearance is a process in which a biopharmaceutical is eliminated from fluid phases, tissues, or organs. With most biopharmaceutical products, clearance is expected to take place through the processes of metabolism and excretion, but first, the molecule must remain in the target tissue or organ long enough for it to have a therapeutic effect. Excretion cannot be too rapid. With many small molecule drugs, the absolute rate of clearance is a linear function of the concentration in blood. However, with biological molecules, this is not always the case, and the rate of clearance is not simply the rate of elimination divided by blood concentration. In addition, while small molecule drugs are often cleared by liver and kidney, larger biological molecules are not often metabolized in the liver and are retained, not excreted, as they pass through the kidney. For many biopharmaceuticals, the sites of metabolism and excretion are unknown, and it is assumed that components of degraded biopharmaceuticals, such as polypeptides, amino acids, and nucleic acids, are simply catabolized to a certain degree and then used by the body to produce energy and to build other macromolecules.
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Published in Valerio Voliani, Nanomaterials and Neoplasms, 2021
Bing Wang, Xiao He, Zhiyong Zhang, Yuliang Zhao, Weiyue Feng
Liver is the main organ of metabolic clearance of most drugs and xenobiotics. Evidence has shown that NMs are preferentially deposited in liver under systemic exposure, resulting in prolonged retention within the organ and in some instances significant hepatotoxicity.28-30 Hepatic lobules, the structural unit of liver, consist of parenchymal cells (i.e., hepatocytes) and nonparenchymal cells, such as Kupffer cells (KCs), sinusoidal endothelial cells, stellate, and intrahepatic lymphocytes. These cells participate in the hepatic clearance pathways of NMs.
Pharmacokinetics Approach for Nanotoxicity Evaluation
Published in Vineet Kumar, Nandita Dasgupta, Shivendu Ranjan, Nanotoxicology, 2018
Drug clearance (CL) can be defined as the elimination of nanodrug concentration in a compartment per unit time. The value for CL is constant for the first order elimination kinetic process. Mathematically, it can be expressed as: CLtotal=k×Vd
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).
Molecular modeling strategy to design novel anticancer agents against UACC-62 and UACC-257 melanoma cell lines
Published in Egyptian Journal of Basic and Applied Sciences, 2023
Abdullahi Bello Umar, Adamu Uzairu
Clearance describes the relationship of the drug concentration in the body to the rate of its elimination. Thus, a lower value of the total clearance implies increased persistence of the drugs in the human body, and all the selected molecules showed good persistence in the body for the drug. Additionally, it is required to investigate whether the designed molecules are nontoxic as this plays a significant role in selecting the best drugs. The results presented in Table 4 indicated that molecule DMB1 is nontoxic. The designed molecules DMB1 and BSN2 displayed good physicochemical and pharmacokinetic ADMET properties. Thus, according to these results, it can be concluded that these molecules can be used as V600E-BRAF inhibitors and drugs against melanoma cancer in the future.
Molecular Docking , ADMET and Pharmacokinetic properties predictions of some di-aryl Pyridinamine derivatives as Estrogen Receptor (Er+) Kinase Inhibitors
Published in Egyptian Journal of Basic and Applied Sciences, 2022
Sagiru Hamza Abdullahi, Adamu Uzairu, Gideon Adamu Shallangwa, Sani Uba, Abdullahi Bello Umar
An indicator, which explains the connection between the elimination rate of drug and its amount in the body, is called total clearance, and the selected compounds displayed higher values of total clearance, which are within the acceptable range of a drug candidate in the body. Additionally, only six (24, 27, 51, 52, 54 and 55) of the compounds possess some level of toxicity. Finally, the selected compounds showed satisfactory physicochemical and pharmacokinetic ADMET properties. Thus, on the basis of these outcomes, it can be acknowledged that these compounds can be embraced as ER+ inhibitors and drugs on breast cancer in the forthcoming years.