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In Vivo Assessment of Dermal Absorption
Published in David W. Hobson, Dermal and Ocular Toxicology, 2020
George J. Klain, William G. Reifenrath
In vivo, systemic uptake can occur via the microcirculation at the epidermaldermal junction of the skin, while in vitro the compound must travel through the dermis (if present) to reach the receptor fluid. Full thickness skin can give results in good agreement with in vivo determinations for relatively hydrophilic compounds (Table 7). For lipophilic compounds (octanol/water partition coefficient ≥1000) the dermis can introduce an artifact by acting as a reservoir or barrier to diffusion into the receptor fluid. Better agreement for these compounds can be obtained by using split thickness skin, and considering residue in the dermis as penetration (Table 7). This was done by isolation and extraction of the dermis at the end of an experiment.58The data in Table 7 also demonstrate the importance of air flow on in vitro penetration measurements. It was necessary to use a higher air flow (600 vs. 60 ml/min) through the evaporation cell to get better agreement for the range of compounds, specifically malathion and N,N-diethyl-m-toluamide, with in vivo values.
Quick Methods: Structure-Activity Relationships and Short-Term Bioassay
Published in Samuel C. Morris, Cancer Risk Assessment, 2020
Another approach is multiparameter analysis. In this, biologic activity is correlated with one or more physical chemical properties of the compound. A common property is the n-octanol/water partition coefficient. The relationship is derived empirically and can hold only for closely related compounds.
Perception, Planning, and Scoping, Problem Formulation, and Hazard Identification
Published in Ted W. Simon, Environmental Risk Assessment, 2019
Of necessity, QSAR requires a prediction model for the biological activity. Often, this is a statistical regression of the predicted value versus the predictor value.182 One of the early uses of QSAR was EPA’s attempt to predict dermal permeability of chemicals from water. Measurements of the dermal permeability coefficient Kp were available for 90 chemicals, and EPA used a regression model to estimate Kp for other chemicals. The independent variables were the octanol-water partition coefficient and the molecular weight. Unfortunately, this regression method did not work for high molecular weight highly lipophilic chemicals, and an effective prediction domain was established inside which the regression was applicable.183
Molecular docking studies, anti-Alzheimer’s disease, antidiabetic, and anti-acute myeloid leukemia potentials of narcissoside
Published in Archives of Physiology and Biochemistry, 2023
Tingting Liu, Lixia Cao, Tingting Zhang, Huan Fu
After comparing the biological activity of narcissoside molecule against enzymes, ADME/T analysis was conducted to theoretically predict the effects and reactions of narcissoside molecule on human metabolism. As a result of this theoretical analysis, many parameters were obtained and these parameters are given in Table 5. The first parameter among these parameters is Solute Molecular Weight, which requires the molecule to have a certain molecular weight. Another parameter is Solute Total SASA, which is the total solvent accessible surface area (SASA) using a 1.4 Å radius probe. Another parameter is QP log p for octanol/water, which is the predicted octanol/water partition coefficient. Another important parameter is QPlogHERG, which is the numerical value of the estimated IC50 value when the HERG K channels are blocked. The next parameter is QPPCaco, which is Caco-2 cell permeability in the gut–blood barrier for inactive transport. Another parameter is QPlogBB, which is the coefficient of the brain–blood barrier of an orally taken drug. The next parameter is #metab, which is the number of Possible metabolic reactions for the afzelin molecule (Demir et al.2020, Kısa et al.2020, Taslimi et al.2020a, 2020b, Türkan et al.2020).
Preparation of an isorhamnetin phospholipid complex for improving solubility and anti-hyperuricemia activity
Published in Pharmaceutical Development and Technology, 2022
Fengmao Zou, Honghui Zhao, Aijinxiu Ma, Danni Song, Xiangrong Zhang, Xu Zhao
The distilled water was added to an equal volume of 1-octanol. The mixed solution was shaken in the air bath thermostatic oscillator at 37 °C for 24 h. The mixture was left to stand for 12 h and then the two phases were collected in the 100 ml conical flask. Next, an excess of ISO or ISO-PC was added to 10 ml of the 1-octanol phase. After being sonicated for 5 min, the solution was centrifuged at 4000 r/min for 15 min. The concentration of the 1-octanol phase (C1) was determined by the UV spectrophotometer. About 1 ml of the above 1-octanol phase was mixed with 1 ml of the aqueous phase and shaken at 37 °C for 24 h to equilibrate the ISO or ISO-PC between the two phases. The two phases were separated by centrifugation, and the aqueous phase was taken to determine the concentration (C2). The octanol-water partition coefficient (P) was calculated by the formula as follows: P = (C1-C2)/C2.
Strategies to optimize drug half-life in lead candidate identification
Published in Expert Opinion on Drug Discovery, 2019
Fabio Broccatelli, Cornelis E.C.A Hop, Matthew Wright
The quantitative relationship between physicochemical properties and biological activities (QSAR) in its modern usage can be considered to have begun in 1964 through the pioneering work of Corwin Hansch [6]. The relevance of physicochemical concepts to drug discovery and development of pharmaceuticals was evaluated and codified as the ‘rule of 5ʹ by Lipinski [17]. The continued appreciation and application of physicochemical principles in drug discovery has contributed to the lower rates of failure of clinical candidates for DMPK-related reasons since 2000 [18]. The attention to physicochemical properties and the identification of ‘drug-like’ chemical spaces has spawned a veritable explosion of correlative analyses between fundamental molecular properties and solubility, permeability, metabolic stability, PPB, receptor promiscuity and toxicity [4,19–26]. Within these analyses, lipophilicity, as expressed by the octanol-water partition coefficient (LogP), continually emerges as a key parameter in relationships between molecular properties and ‘drug likeness’.