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The Measurement of Transport in Vivo Using Radiotracers
Published in Lelio G. Colombetti, Biological Transport of Radiotracers, 2020
With the appropriate choice of the radiotracer based on the application of the well-known principles of drug design, it is possible to measure transport across various vascular beds in vivo. The application of the Se diamines illustrates the pH partition hypothesis in the brain. The use of multiple indicator dilution techniques to measure transport into the intact brain and the lung illustrates a second approach to this problem, either invasively by serial sampling or noninvasively with the gamma camera. Lastly, the use of collimated external probes allows the measurement of the brain extraction of 3-fluorodeoxyglucose and fluorodopa. All of these techniques are relatively simple to apply to experimental studies on the design of new and better radiotracers for the measurement of transport in vivo.
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.
Gastrointestinal Tract as a Major Route of Pharmaceutical Administration
Published in Shayne C. Gad, Toxicology of the Gastrointestinal Tract, 2018
Water-soluble substances usually remain in the blood and interstitial space. Acidic substances tend to bind to various blood protein components such as albumin. On the other hand, lipid-soluble substances tend to collect in adipose tissue and rather than rendering it inactive tend to extend the effect of the substance due to the storage depot effect of these substances. Some other substances are tightly bound to liver and kidney tissues. Equilibrium between blood and the target tissue is reached more rapidly in highly vascularized areas than in poorly perfused areas. At equilibrium, substance concentrations in tissues and in extracellular fluids are reflected by the plasma concentration (Doogue and Polasek, 2013; Smith et al., 2015; Bourne, 2017; Kimball, 2018). The equilibrium pattern of distribution between the various compartments (described below) will depend upon: The permeability across tissue barriersBinding within compartmentspH partitionFat:water partition.
Nicotine forms: why and how do they matter in nicotine delivery from electronic cigarettes?
Published in Expert Opinion on Drug Delivery, 2020
Vinit V Gholap, Leon Kosmider, Laleh Golshahi, Matthew S Halquist
Like e-cigarettes, effect of nicotine form on nicotine’s absorption profile is one of the controversial topics with contradictory research outcomes. Earlier, tobacco companies have been accused of allegedly using alkaline chemical substances such as ammonia or its related basic compounds in manufacturing of cigarettes [40,41]. Their intended purpose was to shift the balance from protonated (NicH+) to free base form (Nic) of nicotine in tobacco for a rapid and efficient absorption of nicotine in consumers [41]. Based upon the pH partition hypothesis of drug absorption, any drug molecule easily penetrates biological membrane (except specific barriers such as Blood Brain Barrier) in an unionized form [42]. Due to its unionized form, free base nicotine is believed to easily cross the biological membrane of the respiratory tract leading to nicotine’s rapid absorption. Additionally, the rapid deposition of free base nicotine in the upper respiratory track was found to have sharp and sudden sensory effects [40,43,44]. This sensory effect was termed as harshness or impact [44].
Cerebrospinal fluid neurotransmitter levels and central nervous system depression in a rat drug overdose model
Published in Toxicology Mechanisms and Methods, 2020
Hiroshi Tsutsumi, Kosei Yonemitsu, Ako Sasao, Yuki Ohtsu, Shota Furukawa, Yoko Nishitani
The drug dose used in this study was sufficient to observe the effects of high-dose drug administration in rats. In the single- and co-administration groups, the serum concentrations of diazepam and phenobarbital were higher than the standard human therapeutic concentrations (diazepam therapeutic concentration range, 200–500 ng/mL; phenobarbital therapeutic concentration range, 10–25 µg/mL) (Yamatogi 1993). The diazepam concentration in serum and CSF increased with phenobarbital co-administration. The phenobarbital concentration was not different between the single-administration and co-administration groups. The mechanism responsible for this phenomenon is unclear. A possible reason for this difference could be that diazepam absorption was promoted by the increased pH of the administration solution, which contained phenobarbital sodium. In general, drug absorption follows the pH partition hypothesis, in which molecular forms are more easily absorbed than ionic forms of drugs (Shore et al. 1957). A basic drug is more likely to be present in its molecular form in a basic solution than in an acidic solution. Both the phenobarbital sodium and diazepam solutions were basic solutions. Thus, when diazepam was in a solution with phenobarbital sodium, more of the drug was in its molecular form than when it was in a solution without phenobarbital sodium. Additionally, drug interactions did not affect the diazepam or phenobarbital distribution in the serum and CSF. The CSF/serum drug concentration ratio did not differ among the drug administration groups.
Nanocrystal: a novel approach to overcome skin barriers for improved topical drug delivery
Published in Expert Opinion on Drug Delivery, 2018
Viral Patel, Om Prakash Sharma, Tejal Mehta
The chemical structure and physicochemical characteristics of the drug molecule are important properties in deciding its permeability through the skin. The diffusivity of the drug molecule through the skin is influenced by its molecular weight. The drugs with molecular weight less than 500 Da show good permeation. Although there are few exceptions, heparin with a molecular weight ̴17,000 Da shows good penetration, which might be due to its own chemical nature [57]. It is observed that there exists an inverse relation between the molecular weight and the absorption rate. The drug molecule with low molecular weight permeates faster despite having similar polarity. With increase in the number of carbon in the structure, there is an increase in lipid solubility of the drug molecule which improves its permeability. The charge of and the charge within the drug molecule also show impact on its penetration. As per the pH partition hypothesis, the nonionized species alone are capable of diffusing through different skin layers. The nonionized molecules are likely to follow intercellular pathway, while the ionized molecules tend to follow intracellular pathway for penetration [56].