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Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Copeland (2011, 2016) described the conformational selection model as an ensemble of conformers in which the enzyme/receptor exists, of which in the absent of an inhibitor/ligand only some few are capable of binding which are in equilibrium with those being unable to bind. Conformers binding an inhibitor are removed from this equilibrium so that more and more ligands become bound. The rate-limiting step in this model is the interconversion between both conformers. Examples of this enzyme-ligand binding interaction are human glucokinase/glucose or α -chymotrypsin/proflavin. In the majority of drug-binding events the induced-fit model becomes effective. The enzyme/receptor is present in a single conformational state that binds the inhibitor or ligand rapidly. Binding is followed by an optimization of the complementarity between the inhibitor molecule and the receptor’s binding pocket via structural adjustments. This comparatively slow conformational transition is the rate-limiting step in this model. Examples are among others cyclooxygenase-1/indomethacin, xanthine oxidase/allopurinol, dihydrofolate reductase/methotrexate, or HIV-1 protease/Darunivir. To sum up, the drug-target residence time is an important aspect for drug optimization by chemists being active in this field.
Pharmacokinetics and Pharmacodynamics of Drugs Delivered to the Lung
Published in Anthony J. Hickey, Sandro R.P. da Rocha, Pharmaceutical Inhalation Aerosol Technology, 2019
Stefanie K. Drescher, Mong-Jen Chen, Jürgen B. Bulitta, Günther Hochhaus
A much more robust parameter than tmax seems to be the estimation of the mean absorption time. This parameter can be readily calculated via non-compartmental analysis by estimating the mean residence time after inhalation (MRTinh) and subtracting the mean residence time after iv administration (MRTiv). This approach is relatively robust, as long as the terminal half-life can be reliably determined. Also, the mean absorption time allows one to characterize the absorption processes among different drugs if iv data are available. For example, differences in the absorption profiles between fluticasone propionate and budesonide can be easily identified with this method, while differences in tmax were not able to readily provide this information. The mean residence time without availability of intravenous data should not be used to compare absorption profiles of different drug entities, as it is also determined by the systemic elimination of the drug. The use of the mean residence time is, however, suitable for evaluating the differences in absorption of different formulations of the same drug.
Peritoneal drug transport
Published in Wim P. Ceelen, Edward A. Levine, Intraperitoneal Cancer Therapy, 2015
In the perioperative setting, drug delivery can be enhanced considerably. Two or more catheters can be placed in the peritoneal cavity: one or more catheters for drug input and the other catheter(s) for removal of solution. Solutions warmed to temperatures greater than body temperature (approximately 41°C) may be infused rapidly into the peritoneal cavity and withdrawn in the second catheter. This technique will set up higher concentrations if solution is fed from a large reservoir that the loss of drug is relatively small. Heating of the drug causes vasodilation in the surrounding vessels, and there is likely an increase in penetration into both normal tissue and neoplastic tissue [89–93]. Other methods include the surgeon massaging/stirring the treatment solution in situ within the cavity [94]. Either of these techniques may help to solve the problem of residence time. If a greater portion of the peritoneal surface area is covered by the solution and the concentration of the drug is maintained constant, then the area into the curve for the surface contact concentration should be maximized. Randomized controlled trials of these techniques will help in the decision to implement the additional procedures [95].
Influence of process temperature and residence time on the manufacturing of amorphous solid dispersions in hot melt extrusion
Published in Pharmaceutical Development and Technology, 2022
Tobias Gottschalk, B. Grönniger, E. Ludwig, F. Wolbert, T. Feuerbach, G. Sadowski, M. Thommes
For the formulation screening, three parameters (residence time, drug weight fraction and process temperature) were varied within this study. Three different drug concentrations were investigated (Table 1). The temperatures were set in specific differences (0, ±3, ±7, and ±10 K) to solubility temperatures for the equilibrium state predicted by PC-SAFT (see Table 1), which was used as a reference temperature in this work. The residence time was varied between the continuous operating mode (<1 min) and specific residence times (1, 3, and 10 min) by utilizing of the recirculation channel. For each combination of process temperature, residence time and drug weight fraction, the extrusion was performed once. However, experiments close to the solubility temperature were performed in triplicate since the literature indicated a phase change at this temperature.
Evolution of the drug-target residence time model
Published in Expert Opinion on Drug Discovery, 2021
A number of studies have been reported that attempt to understand the structural determinants of drug-target residence time with the goal of ‘tuning’ the residence time to meet the in vivo needs of a particular therapeutic effect (see, for example [46],). Other studies have attempted to understand the contributions of ground state and transition state enthalpic and entropic components to residence time (see, for example [47],). Still other studies attempt to use computational molecular dynamics methods to divine the escape trajectory of drug dissociation from a target protein, again with the aim of defining the structural elements of rate-limiting steps in drug escape (see, for example [48],). Space does not permit a comprehensive review of these important studies, but many of these have been covered in recent reviews [49,50].
Sulpiride gastro-retentive floating microsponges; analytical study, in vitro optimization and in vivo characterization
Published in Journal of Drug Targeting, 2020
Mahmoud A. Younis, Marwa R. El-Zahry, Mahmoud A. Tallat, Hesham M. Tawfeek
SUL plasma concentration versus time curve was plotted and the pharmacokinetics were calculated as previously reported [1,6,33]. Cmax and Tmax were directly-determined from the curve. The method of residual was adapted to obtain the rate constant of absorption (Kabs). The slope of the terminal linear portion of the curve was used to calculate the elimination rate constant (Kel.) from the linear regression analysis. The apparent half-lives of absorption and elimination (t½) were obtained via dividing 0.693 by the corresponding rate constant. Furthermore, the area under plasma concentration-time curve from zero to end time (AUC0–t) and the area under first moment curve from zero to end time (AUMC0–t) were calculated using linear trapezoidal rule. AUC and AUMC from zero-time to infinity (AUC0–∞ and AUMC0–∞) were calculated by Equations 3 and 4, respectively. t is the last measurable concentration at the end time point (t), Kel. is the elimination rate constant of drug. The mean residence time of the drug in the body (MRT) was calculated using Equation (5).