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Treatments and Challenges
Published in Franklyn De Silva, Jane Alcorn, The Elusive Road Towards Effective Cancer Prevention and Treatment, 2023
Franklyn De Silva, Jane Alcorn
Studies evaluating the nutritkinetics (or pharmacokinetics (PK), the study of what the body does to the xenobiotic) [1357, 1358] and nutridynamics (or pharmacodynamics (PD), the study of what the xenobiotic does to the body) [1359] have provided critical understanding of the putative role of natural products in cancer treatment and prevention. As an area of study, nutrikinetics can additionally address the compositional complexity of dietary ingredients, types of diets, interindividual variation, metabolic profiling, interactions between the host metabolome and the microbiome as well as absorption, distribution, metabolism, and excretion of dietary items within the organism [1359] . When a xenobiotic results in toxicity, toxicokinetics is a term used to describe the processes by which the compound reaches a target tissue, while the subsequent responses that take place in the tissue once the toxic xenobiotic reaches an effective dose is called toxicodynamics [1360]. Understanding and describing the relationship between a natural product compound's pharmacophore (i.e., the three-dimensional, steric and electronic features that are required to guarantee an optimal supramolecular interaction with a biological target to display a response(s) [1361]) and its intended target(s) and/or off-targets with their cumulative dynamic effects on cells, tissues, organs, and an entire organism as well as the rate and extent of its absorption, distribution, and elimination is central to understanding the overall ability of a natural product to exert positive pharmacological outcomes in cancer.
Approaches for Identification and Validation of Antimicrobial Compounds of Plant Origin: A Long Way from the Field to the Market
Published in Mahendra Rai, Chistiane M. Feitosa, Eco-Friendly Biobased Products Used in Microbial Diseases, 2022
Lívia Maria Batista Vilela, Carlos André dos Santos-Silva, Ricardo Salas Roldan-Filho, Pollyanna Michelle da Silva, Marx de Oliveira Lima, José Rafael da Silva Araújo, Wilson Dias de Oliveira, Suyane de Deus e Melo, Madson Allan de Luna Aragão, Thiago Henrique Napoleão, Patrícia Maria Guedes Paiva, Ana Christina Brasileiro-Vidal, Ana Maria Benko-Iseppon
The main preclinical toxicological tests that are requested internationally are based on the international guides of the International Council for Harmonization (ICH) number M3 (R2) from the Food and Drug Administration (FDA 2013) and of the European Medicine Agency (EMA 2013). Tests are conducted in vitro using cell culture or in vivo involving rodents and other mammals (Fig. 10.2). In general, preclinical trials assess the toxicity in different model organisms at diverse levels. Acute toxicity in a single dose or repeated doses and reproductive toxicity generally assess how the compound acts in various organ systems in mice, including reproductive organs (in vivo). Genotoxicity and carcinogenicity tests assess the compound’s ability to induce DNA damage and develop a tumor, respectively. Local toxicology observes whether the drug induces an undesirable reaction in the contact region. Pharmacodynamics is an observation of the effects of the compound on organ systems, emphasizing the central nervous, cardiovascular and respiratory systems. Finally, toxicokinetic observes the pathway of the compound throughout the body, including absorption, metabolism and excretion. So far, genotoxicity and toxicokinetic tests can be conducted in vitro (Sjöberg and Jones 2013; Denny and Sterwart 2017; Madia et al. 2021).
A Risk Analyst’s Toolbox
Published in Ted W. Simon, Environmental Risk Assessment, 2019
Pharmacokinetics is the study of the quantitative relationships between the absorption distribution, metabolism, and elimination (ADME) of chemicals in biological systems. This study is also called toxicokinetics when applied to toxic chemicals. Pharmacokinetic models were first used in the early 20th century to describe the absorption and elimination of alcohol and ether from the blood.34 PBPK models are mathematical representations of biological tissues, organs, and physiological processes occurring in the body and affecting the absorption, distribution, metabolism and excretion of chemicals.
Evaluation of genotoxicity induced by herbicide pendimethalin in fresh water fish Clarias batrachus (linn.) and possible role of oxidative stress in induced DNA damage
Published in Drug and Chemical Toxicology, 2022
Priyanka Gupta, Sushant Kumar Verma
Determination of median lethal concentration (LC50) can be considered as most useful criterion of toxicity. The 96 h- LC50 value of pendimethalin for C. batrachus was determined as 3.55 mg/L which is similar to those obtained by Ahmad et al. (2000) in Nile tilapia (3.55 mg/L). However it was found to be 0.19 mg/L in bluegill sunfish and 0.138 mg/L in rainbow trout (USEPA 1996). These observed differences in obtained values of LC50 for different species were may be due to age, size and health (Abdul Farah et al. 2004) or physico-chemical parameters of water (Eaton and Gilbert 2008). LC50 of different toxicants may also differ with different species because of differences in toxicokinetics as well as toxicodynamics between the species (Rubach et al. 2011). Toxicokinetics include ability of a species to regulate the uptake of toxicant, detoxify it and finally eliminate it whereas toxicodynamics include interaction of the toxicant with enzymes and ability to repair damage. Concentration and formulation of chemicals are also important factors which can be considered during determination of median lethal concentration of a toxicant (Young and Woodside 2001).
Plasma protein binding, metabolism, reaction phenotyping and toxicokinetic studies of fenarimol after oral and intravenous administration in rats
Published in Xenobiotica, 2021
Kajal Karsauliya, Ashish Kumar Sonker, Manisha Bhateria, Isha Taneja, Anshuman Srivastava, Manu Sharma, Sheelendra Pratap Singh
Toxicokinetic evaluation of a chemical is a regulatory as well as scientific requirement in human health risk assessment. Toxicokinetics provides imperative information concerning the ADME (absorption, distribution, metabolism, excretion) process and characteristics of toxic substances in the animal. It is the concentration of a chemical in the systemic circulation that is responsible for eliciting the toxic effects in an organism (Bessems & Geraets, 2013; OECD, 2010). Thus, knowledge regarding systemic exposure about a chemical could play a major role in construing the toxicity studies. Further, the availability of preclinical toxicokinetic data assists in reducing the uncertainty in human health risk assessment based on preclinical toxicity studies (Coecke et al., 2013; Creton et al., 2009; OECD, 2010; Sewell et al., 2017).
Metabolism and disposition of 2-hydroxy-4-methoxybenzophenone, a sunscreen ingredient, in Harlan Sprague Dawley rats and B6C3F1/N mice; a species and route comparison
Published in Xenobiotica, 2020
Esra Mutlu, C. Edwin Garner, Christopher J. Wegerski, Jacob D. McDonald, Barry S. McIntyre, Melanie Doyle-Eisele, Suramya Waidyanatha
Absorption, distribution, metabolism, and excretion (ADME) and toxicokinetic (TK) studies are crucial in the interpretation of toxicology data. While there are some ADME data for HMB available in the literature for rats (male Sprague Dawley (SD), F344/N) and mice (male B6C3F1) there are neither disposition nor metabolism data in female rats or female mice. HMB is rapidly absorbed regardless of dose route in male rats and piglets (El Dareer et al., 1986; Jeon et al., 2008; Kadry et al., 1995; Kasichayanula et al., 2007; Okereke et al., 1993). Limited studies following oral (3–293 mg/kg) and IV (4.63 mg/kg) administration of [14C]HMB to male F344/N rats showed excretion of 64–67% and 23–42% in urine and feces, respectively within 72 h. (El Dareer et al., 1986). After dermal application to F344/N rats, approximately 39% and 22% of the applied dose was excreted in urine and feces (El Dareer et al., 1986). In the same study, approximately 1% of the oral and IV doses remained in all surveyed tissues and in gastrointestinal (GI) contents at 72 h, with extensive excretion of radioactivity in bile (37% within 4 h) following IV administration (4.46 mg/kg). In another study, following oral administration of HMB (100 mg/kg) in SD rats, the liver contained the highest amount of free and total HMB, followed by kidney, and testes (Kadry et al., 1995).