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An Introduction to Risk Assessment with a Nod to History
Published in Ted W. Simon, Environmental Risk Assessment, 2019
Mathematical modeling of the distribution of chemicals in the body is also known as physiologically based toxicokinetic modeling. It is also known as ADME modeling, where ADME stands for Absorption, Distribution, Metabolism, and Excretion. Simply, PBPK modeling is a way of dividing up the body into functional compartments into which chemicals may accumulate or be metabolized and excreted. One of the best-known PBPK models is the Widmark model—this simple one-equation model is used for retrograde extrapolation of measured blood or breath alcohol levels in forensic evaluation of potential drunk driving cases. The Widmark model assumes the body is a single compartment and that elimination of alcohol occurs by a zero-order kinetic process. What this means is that a constant amount of alcohol is metabolized and excreted per time unit.
Pharmacokinetics and Pharmacodynamics of Drugs Delivered to the Lung
Published in Anthony J. Hickey, Sandro R.P. da Rocha, Pharmaceutical Inhalation Aerosol Technology, 2019
Stefanie K. Drescher, Mong-Jen Chen, Jürgen B. Bulitta, Günther Hochhaus
Physiologically based pharmacokinetic as shown in Figure 6.14 or semi-mechanistic modelling approaches have been used as an emerging tool within drug development for predicting the in vivo fate of drugs from in vitro/in silico assessments of the drug candidate with the goal of predicting absorption, distribution, metabolism, and excretion of a drug candidate (ADME) (Barnes et al. 1998; Rowland et al. 2011; Zhao et al. 2011; Gaohua et al. 2015). The mechanistic basis of this approach allows predictions considering the effects of the patient’s age, genetics, and disease or characteristics of the drug formulation on ADME characteristics. This has been accomplished by building up a mathematical model that can describe the fate of the drug as close as possible to the actual processes responsible for absorption, distribution, metabolism, and elimination. The ultimate goal is to provide a broader physiological understanding of the drug’s fate via a compartmental modelling approach. Semi-mechanistic approaches are somewhat less complex and attempt only to model part of the drug’s ADME within the physiological context. The main purpose of this approach, once established, is to predict the drug’s fate including drug-drug interactions, effects of formulations on drug absorption, thereby facilitating drug development, e.g. by facilitating the design of clinical studies.
Overview of Drug Development
Published in Mark Chang, John Balser, Jim Roach, Robin Bliss, Innovative Strategies, Statistical Solutions and Simulations for Modern Clinical Trials, 2019
Mark Chang, John Balser, Jim Roach, Robin Bliss
Pharmacokinetics is often studied in conjunction with pharmacodynamics. Pharmacodynamics explores what a drug does to the body, whereas pharmacokinetics explores what the body does to the drug. Specifically, pharmacokinetics is the study of drug Absorption, Distribution, Metabolism, and Excretion (ADME). Absorption is the process of a substance entering the body. Distribution is the dispersion or dissemination of substances throughout the fluids and tissues of the body. Metabolism is the irreversible transformation of parent compounds into daughter metabolites. Excretion is the elimination of the substances from the body. In rare cases, some drugs irreversibly accumulate in a tissue in the body.
Impact of DNA methylation on ADME gene expression, drug disposition, and efficacy
Published in Drug Metabolism Reviews, 2022
Xu Hao, Yuanyuan Li, Jialu Bian, Ying Zhang, Shiyu He, Feng Yu, Yufei Feng, Lin Huang
The pharmacokinetic process includes the absorption, distribution, metabolism, and excretion (ADME) of drugs in organisms. The expression of ADME genes such as transporters, phase I metabolic enzymes, phase II metabolic enzymes, and nuclear receptors affect the effectiveness and safety of drugs via intervening in drug disposal. It is well known that the expression of drug-metabolizing enzymes and transporters is affected by genetic polymorphism and nuclear receptors (Johansson and Ingelman-Sundberg 2011; Sissung et al. 2012; Xu et al. 2018), which can only explain some of the interindividual differences in clinical treatment (Bonder et al. 2014; Xu et al. 2018). Kacevska et al. suggested that the ADME genes undergo epigenetic regulation (Kacevska et al. 2011). Epigenetics is not the study of the effects of DNA sequence changes on gene expression. Epigenetic regulation leads to relatively stable changes, which are usually affected by age, diet, lifestyle, disease, and environment (Peng and Zhong 2015). The mechanisms of epigenetic regulation of ADME gene expression include DNA methylation, histone modification and non-coding RNAs (Hirota et al. 2017).
The metabolism and excretion of the dipeptidyl peptidase 4 inhibitor [14C] cetagliptin in healthy volunteers
Published in Xenobiotica, 2022
Jinmiao Lu, Yicong Bian, Hua Zhang, Dong Tang, Xusheng Tian, Xinyi Zhou, Zengyan Xu, Yating Xiong, Zheming Gu, Zhenwen Yu, Tong Wang, Juping Ding, Qiang Yu, Jinsong Ding
When drugs are administered to living organisms, they undergo a series of events such as absorption, distribution, metabolism and excretion (ADME) and these events modulate the efficacy and toxicity of drugs. Understanding the clearance mechanism, distribution and the metabolic fate of a drug candidate in humans is a key factor in new drug development, registration and ultimate use. in addition to good pharmacological activity, ADME properties are crucial determinants of the ultimate clinical success of a drug candidate. Labelling compounds with carbon-14 or H-3 (tritium) is by far the most widely used technique and the choice is usually between these two isotopes when planning a human mass balance study (Penner et al. 2009). However, the pros of the tritium use are outweighed by the cons, notably, the lack of biological stability and isotopic effect (switching biotransformation pathway due to reaction kinetics) (Shaffer et al. 2006). In a drug development setting, 14C-labelling is used in the majority of ADME studies (Penner et al. 2009).
Preclinical in vitro screening of newly synthesised amidino substituted benzimidazoles and benzothiazoles
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Livio Racané, Maja Cindrić, Ivo Zlatar, Tatjana Kezele, Astrid Milić, Karmen Brajša, Marijana Hranjec
ADME properties are dependent of structural characteristics of newly synthesised molecules. Different modifications are undertaken and tested during early drug discovery in order to achieve better and improved drug-like properties30. ADME characterisation represents an important step in the drug discovery process and it includes several in vitro assays covering physicochemical and biochemical properties such as solubility, lipophilicity, permeability, metabolic stability and binding to plasma proteins31. Here, we have evaluated major ADME properties to see if compound’s activity, obtained in 3 D cell cultures, is the consequence of different physicochemical and biochemical properties in comparison with non-active compounds, as well as to see if compounds have drug-like properties and potential for further profiling in in vivo models.