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Inhalation Toxicity of Metal Particles and Vapors
Published in Jacob Loke, Pathophysiology and Treatment of Inhalation Injuries, 2020
These agents are essentially nontoxic except for beryllium, which is used to make durable steel, and in the nuclear and electronic industries. In the past, it was used widely in the manufacture of fluorescent lights and neon signs. Beryllium is highly toxic if inhaled and causes fever and progressive lung fibrosis. Beryllium inhibits enzyme activity, particularly that of alkaline phosphatase, but acts mainly by inducing a hypersensitivity response. Its toxicity is enhanced by its small molecular size which results in greater tissue penetration, its high charge to mass ratio, and the absence of a homeostatic control mechanism. Lung fibrosis is known to be associated with lung cancer. Magnesium and calcium are metals of major importance in normal body function and only cause toxicity at high dosage, usually because of existing internal disease rather than from excessive intake.
Development of Topical and Transdermal Dosage Forms
Published in Tapash K. Ghosh, Dermal Drug Delivery, 2020
The skin is one of the most extensive and readily accessible organs but serves as a barrier to the environment surrounding us. It is elastic, rugged and under normal physiological conditions, self-generating1. Drug development, either for topical or transdermal products, represents an added layer of both complexity and opportunity for the drug developer and clinician. Even though transdermal drug delivery takes advantage of the relative accessibility of the skin, only a small number of drug products are currently available via this route of administration. In many cases, a drug’s physical properties, including molecular size and polarity, limits its capacity to be delivered across skin. Similarly, the biological properties of drug molecules including dermal irritation/sensitization and insufficient bioavailability due to limited skin permeability have posed additional constraints to this delivery technology. Irritation and sensitization can be caused by the drug, the adhesive or other excipients on the skin from the applied formulation. Still, there are a number of notable examples of successful transdermal products on the market. Approved transdermal systems include clonidine, estradiol, estrogen/progestin, fentanyl, methyl salicylate, methylphenidate, nicotine, nitroglycerin, oxybutynin, rivastigmine, rotigotine, selegiline, scopolamine and testosterone. In recent years several Investigational New Drug (IND) Applications have been received by the Food and Drug Administration.
Toxicokinetics
Published in Frank A. Barile, Barile’s Clinical Toxicology, 2019
As noted earlier, the distribution of a drug or chemical is influenced by a variety of dynamic features. Regardless of concentration, when a drug meets the two minimum conditions for distribution—namely, relatively minor size of the molecule and high water solubility—then the main requirements for favorable absorption and distribution are satisfied. If molecular size and solubility were the only important criteria, however, then most drugs would traverse biomembranes without the prerequisite of carrier proteins or active transport. In addition, the presence of charges on drug molecules affects ionization, association, dissociation, and eventually, unequal distribution and passage through membranes. Consequently, other factors that shape the distribution of chemicals into physiologic compartments are listed and briefly described in Table 10.8. These include the pH partition principle, the electrochemical and Donnan distribution effect, binding and storage, and nonequilibrium and redistribution. These principles are not functionally independent of other pressures but contribute to determining distribution kinetics. Further discussion of these factors is found in the Suggested Readings.
Experimental and computational models to investigate intestinal drug permeability and metabolism
Published in Xenobiotica, 2023
Jinyuan Chen, Ziyun Yuan, Yifan Tu, Wanyu Hu, Cong Xie, Ling Ye
Among the various routes of drug delivery, the oral route is the most widely adopted because of its simplicity, non-invasiveness, and easy preservation of drugs. Therefore, achieving optimal efficacy and bioavailability of oral drugs is an important goal (Zietek et al. 2021). This requires intestinal models that can fully reproduce the factors that interfere with drug absorption and metabolism. These factors are complex and include the physicochemical characteristics of the drug itself, as well as the intestinal physiological conditions (Fedi et al. 2021). In terms of the drug itself, the molecular size, liposolubility, solubility, dissociation, and formulation are the main characteristics that affect drug absorption and metabolism. As such, these factors should be carefully considered during the process of drug design. However, this review focuses on intestinal models. Therefore, the effects of drug characteristics will not be described in detail.
Subcutaneous catabolism of peptide therapeutics: bioanalytical approaches and ADME considerations
Published in Xenobiotica, 2022
Simone Esposito, Laura Orsatti, Vincenzo Pucci
SC absorption is affected by multiple factors including peptide physicochemical properties, physiological processes, and biological environment. The complex interplay of these aspects, not yet fully understood, was discussed in several reviews, that have also highlighted differences and similarities between smaller peptides and larger proteins (Richter et al. 2012; Richter and Jacobsen 2014; Tibbitts et al. 2016; Sequeira et al. 2019). A comprehensive overview of the impact of physicochemical properties on peptide SC delivery has recently been provided by Klepach et al. (Klepach et al. 2022). Molecular size is one of the most important determinants of absorption after SC administration influencing uptake by blood capillaries or lymph vessels. The charge of the peptide is also important due to the slightly negative charge present in the interstitial space. Some of the other relevant determinants are protein binding, dose, and administration vehicle and all together affect absorption and the extent of catabolism at the injection site.
Developments in the discovery and design of intranasal antidepressants
Published in Expert Opinion on Drug Discovery, 2020
Małgorzata Panek, Paweł Kawalec, Andrzej Pilc, Władysław Lasoń
The transport of particular molecules from the nose to the brain may be restricted by an enzymatic barrier, mucociliary clearance, protective barriers, and low bioavailability. Cytochrome P450–dependent monooxygenase, carboxyl esterase, and aminopeptidase are examples of enzymes present in the nasal mucosa. They may decrease the transport of various proteins or peptides across the nasal membrane. They also create a pseudo-first-pass effect because the transported molecules undergo enzymatic degradation in the nasal cavity or nasal epithelium. Mucociliary clearance is a self-clearing mechanism that is responsible for the rapid removal from the body of particles caught from the nasal mucosa. It is considered to be a protective temporal barrier that limits the absorption of drug across the nasal epithelium. To overcome this barrier, some bioadhesive materials are added to drug formulations. Another protective barrier is the physical barrier of the nasal membrane. The low bioavailability of drugs is a considerable problem. This applies in particular to polar drugs with a large molecular size. While lipophilic drugs have a bioavailability of almost 100%, the bioavailability of polar substances is estimated at about 10%. To improve the permeability of polar drugs, an absorption enhancer could be added to drug formulation [20].