In Vitro to In Vivo Extrapolation of Metabolic Rate Constants for Physiologically Based Pharmacokinetic Models
John C. Lipscomb, Edward V. Ohanian in Toxicokinetics and Risk Assessment, 2016
When using in vitro systems to investigate toxicological problems, care should be taken to insure that the incubation conditions are physiologically meaningful. Whenever possible, in vitro experiments should be done at physiological pH (7.2–7.4) and temperature (37°C). Ionic strength is another experimental variable that can affect the rates of enzyme-catalyzed reactions. As indicated in Eq. (1), the initial rate of the enzymic reaction should be a linear function of the enzyme concentration (or added protein or cell number) and time. When these requirements are satisfied, initial rate conditions have been achieved (6). Comparisons of the rates of enzyme-catalyzed reactions obtained outside the range of initial rate conditions are not valid. This is a pitfall of mining data from some older biomedical literature. Sometimes during the physicochemical characterization of an enzyme or a xenobiotic metabolism pathway, apparent kinetic parameters for the reaction being studied are reported from studies that were improperly or incompletely done. It is imperative to review the experimental details of the study in the experimental procedures section of the publication. Results presented without sufficient experimental detail to understand how they were derived should be treated with skepticism and probably should not be used in PBPK models or quantitative risk assessments.
Drug Nanocrystals
Carla Vitorino, Andreia Jorge, Alberto Pais in Nanoparticles for Brain Drug Delivery, 2021
To prevent aggregation, nanocrystallisation must be carried out in the presence of stabilisers [121]. These are adsorbed at the particle surface and stabilisation may be achieved by electrostatic repulsion among particles, by steric effects, or by a combination of both. Electrostatic stabilisers typically include ionic surfactants and polymers (e.g., sodium dodecyl sulphate [122, 123], sodium alginate [54]) [124–126]. For electrostatic stabilisation of nanocrystals, the zeta potential should be in excess of 30 mV [1]. Concerning brain delivery, some authors report that negatively charged particles should be used, as highly positively charged nanoparticles displayed toxicity to the BBB [127]. Electrostatic stabilisation is effective in aqueous media, but problems may arise when converting into dry solid forms. Moreover, stability may also be affected by changes in both pH and ionic strength. Steric stabilisation is not dependent on these effects, although it shows a greater temperature dependency [1], and may be used to prepare nanocrystals both in aqueous and non-aqueous media. For steric stabilisation, non-ionic amphiphilic surfactants or polymers are used (e.g., Tween 80, poloxamers, polyvinyl alcohol, polyvinylpyrrolidone [123–125]). Nanosuspensions may also be made more stable by combining electrostatic and steric effects in the same stabiliser molecule [118] or combining non-ionic and ionic stabilisers [128].
Solid-Phase Extraction Disks: Second-Generation Technology for Drug Extractions
Steven H. Y. Wong, Iraving Sunshine in Handbook of Analytical Therapeutic Drug Monitoring and Toxicology, 2017
A general review of guidelines established for use of the various sorbent types can assist method development with the disk. For extractions using reversed-phase sorbents, the sample environment (pH, ionic strength) is adjusted to promote an uncharged (neutral) form of the analyte. Increasing the ionic strength of the sample matrix can sometimes “salt-out” the more polar analytes and improve recovery. For ion-exchange sorbents, the sample matrix is adjusted such that one charged species predominates so the analyte is able to interact efficiently with charged ligand of the sorbent. Herein, the pH is adjusted to 2 units above pKa of anions, 2 units below pKa of cations, and the ionic strength should be low. With normal-phase (mode) sorbents, the analyte requires a nonpolar environment to facilitate interaction with the bonded polar ligands or native silanols present on the silica support.
Solubilization of the chlorin TPCS2a in the presence of Pluronic® F127/Tween 80 mixtures
Published in Pharmaceutical Development and Technology, 2019
Nicola Cuccato, Luca Nardo, Solveig Kristensen, Hanne Hjorth Tønnesen, Marianne Lilletvedt Tovsen
Aqueous samples of TPCS2a (c = 1 µM; n = 3) at pH 2.9 and pH 7.4 were prepared by the addition of HCl and NaOH, respectively, to MilliQ water. The ionic strength was kept constant at the value µ = 0.01 M by the addition of NaCl. These samples were made in order to evaluate the PS as a free base and zwitterion, respectively, by absorption and fluorescence measurements, in analogy with previous works (Lilletvedt et al. 2011a; Nardo et al. 2012a). The efficacy of the surfactant mixtures of Pluronic® F127/Tween 80 (molar ratios 1:1, 1:10, and 10:1, respectively) to prevent PS aggregation was assessed at pH 2.9, where TPCS2a exists as a zwitterion, both below and above the above-determined CMC value, i.e. at 0.1 µM and 1 µM, respectively (vide infra). In the case of the molar ratio 10:1 Pluronic® F127/Tween 80 mixture, complete disaggregation was not achieved even at 1 µM overall surfactant concentration and thus, additional experiments were performed at higher overall concentration for this mixture until complete TPCS2a monomerization was achieved.
Real-time monitoring of cellular oxidative stress during aerosol sampling: a proof of concept study
Published in Drug and Chemical Toxicology, 2022
Lynn E. Secondo, Vitaliy Avrutin, Umit Ozgur, Erdem Topsakal, Nastassja A. Lewinski
Measurements can be affected by the ionic strength of the electrolyte, observed through the response in PBS. A 100× increase in ionic strength (I) was observed as a similarly proportional increase in current. The ionic strength of 1 M PBS and HBSS are very similar, IPBS, 1 M = 152 mM and IHBSS=155 mM. Additional ions within the electrolyte may affect the ability to shuttle ions as there is more affinity to the solution than at low ionic concentrations. This is consistent with the findings of Avila et al. (2000) solutions of low ionic strength provided near independence of electron transfer. The Nafion membrane is cation permeable and diffusion relates to the cation charge and concentration of solution, therefore as HBSS has calcium and magnesium ions in solution, the sensor response is reduced compared to 1 M PBS, at 1 V and 0.1 µM H2O2 the currents are 74 µA and 1095 µA, respectively. Temperature, electrolytic compounds, and pH have also been shown to affect sensor response (Cai et al.1995, Allen et al.1997, Avila et al.2000).
Potential factors affecting free base nicotine yield in electronic cigarette aerosols
Published in Expert Opinion on Drug Delivery, 2021
Vinit V. Gholap, Adam C. Pearcy, Matthew S. Halquist
Secondly, the post-vaporization e-cigarette aerosol is a highly unstable phase thus necessitating the collection of the aerosol on a stable medium before analysis. One of the major advantages of the Henderson–Hasselbalch method is that the method provides a stable medium for collecting the aerosol for analysis. Despite these advantages, the current limitations of the overall study are those of the Henderson–Hasselbalch method that have been described in detail in our earlier study [8]. To summarize these limitations, the method provides a ‘relative’ scale of free base nicotine determination and is limited by unknown ionic concentration of the e-liquid solution as well as an arbitrary factor of dilution. As of now the contents of the e-liquids are not displayed and it is not possible to determine the ionic concentration of the solvent after dilution. Nevertheless, the activity coefficient of [H+] ions does not change significantly (0.96 to 0.83) over the range of 0.001 to 0.1 M of ionic strength [31]. Additionally, this activity coefficient is used in the log form in the Henderson-Hasselbalch equation [8]. Therefore, variation in the ionic concentration post-dilution/post-vaporization are not expected to affect the free base nicotine calculations significantly.
Related Knowledge Centers
- Chemical Compound
- Dissociation Constant
- Solution
- Ion
- Dissociation
- Electrolyte
- Salt
- Activity Coefficient
- Magnesium Sulfate
- Debye–Hückel Theory