Extent Of Drug Binding Research Articles

Characterization of benzodiazepine binding site on human α1-acid glycoprotein using flunitrazepam as a photolabeling agent

The binding of flunitrazepam (FNZP) by human alpha1-acid glycoprotein (hAGP) and the relationships between the extent of drug binding and desialylation and the genetic variants of hAGP were examined. The photolabeling specificity of [3H]FNZP was confirmed by findings in which other hAGP-binding ligands inhibited the formation of covalent bonds between [3H]FNZP and hAGP. The photolabeling of asialo-hAGP suggested that sialic acid does not involve in the binding of [3H]FNZP. No difference in the labeling could be found between the F1*S variants and A variant. Similarly, FNZP did not show a difference in binding affinity to the two genetic variants of hAGP. Sequence analysis of the photolabeled peptide indicated a sequence corresponding to Tyr91-Arg105 of hAGP.

Enantioselective Binding of Propranolol, Disopyramide, and Verapamil to Human α1‐Acid Glycoprotein

We investigated the binding of propranolol (PL), disopyramide (DP), and verapamil (VP) enantiomers by human α1‐acid glycoprotein (AGP; also called orosomucoid) and the relationships between the extent of drug binding and lipophilicity, desialylation, and genetic variants of AGP. Desialylation had little effect on the affinity of AGP for the drugs tested. The percentage binding correlated significantly with the partition coefficients for the drugs tested. Each enantiomer was competitively displaced from AGP by another enantiomer of the same drug, suggesting that they bind to the same site. However, the enantiomers bound to AGP with stereospecific affinities; the (−)‐isomers of DP and VP had higher Kd values (4.27 and 4.97 μM, respectively) than the (+)‐isomers (1.51 and 2.48 μM, respectively). When enantiomers of the different drugs were used in competitive binding experiments, VP binding was only partially inhibited by DP. This result suggested that drug binding is specific to different variants of AGP (A, F1, S). DP was found to specifically bind to variant A, whereas PL and VP bind to both A and F1/S variants. © 2000 Wiley‐Liss Inc. and the American Pharmaceutical Association J Pharm Sci 89:751–757, 2000

Considerations on pharmacodynamics and pharmacokinetics: Can everything be explained by the extent of drug binding to its receptor?

It is frequently assumed that pharmacological responses depend solely on the extent of drug binding to its receptor according to the occupational theory. It is therefore presumed that the intensity of the effect is determined by drug concentration at its receptor site, yielding a unique concentration-effect relationship. However, when dependence, abstinence, and tolerance phenomena occur, as well as for pharmacological responses in vivo that are modulated by homeostatic mechanisms, the rate of drug input shifts the concentration-effect relationship. Hence, such responses cannot be explained on the sole basis of the extent of drug binding to its receptor. Information on the cellular and molecular processes involved in the generation of abstinence, dependence, and tolerance will undoubtedly result in the development of pharmacodynamic models allowing a satisfactory explanation of drug effects modulated by these phenomena. Notwithstanding, integrative physiology concepts are required to develop pharmacokinetic-pharmacodynamic models allowing the description of drug effects in an intact organism. It is therefore important to emphasize that integrative physiology cannot be neglected in pharmacology teaching and research, but should be considered as an equally valuable tool as molecular biology and other biomedical disciplines for the understanding of pharmacological effects.

Considerations on pharmacodynamics and pharmacokinetics: Can everything be explained by the extent of drug binding to its receptor?

Considerations on pharmacodynamics and pharmacokinetics: Can everything be explained by the extent of drug binding to its receptor?

Propranolol Hydrochloride Binding in Calcium Alginate Beads

The interaction of propranolol hydrochloride with alginate molecular chains in calcium alginate beads was investigated. The drug was either incorporated into formed calcium alginate gel beads or incorporated simultaneously with the gelation of alginate beads by Ca2+. Bed produced by the former method had a higher drug content and lower Ca2+ level compared to those prepared by the latter method. The extent of drug binding to the alginate molecules increased with decreasing Ca2+ levels in the beads, indicating that propranolol and Ca2+ shared common binding sites in the alginate chains, me appearance of the beads and the molphology of the alginate polymer in the beads were affected by the amounts of both propranolol and Ca2+ in the beads. Differential scanning calorimetry (DSC) analyses showed that the formation of the calcium alginate gel structure was impeded in the presence of propranolol molecules.

Temperature dependent binding of mebendazole to tubulin in benzimidazole-susceptible and -resistant strains of Trichostrongylus colubriformis and Caenorhabditis elegans

The binding of [ 3H]mebendazole ([ 3H]MBZ) to tubulin in benzimidazole-susceptible (BZ-S) and benzimidazole-resistant (BZ-R) strains of Trichostrongylus colubriformis and Caenorhabditis elegans was examined in order to investigate the biochemical changes to tubulin that result in BZ resistance in parasitic and free-living nematodes. In both species the extent of [ 3H]MBZ binding to tubulin was significantly reduced in the BZ-R strain compared with the BZ-S strain. The decrease in [ 3H]MBZ binding in the BZ-R strain of each species was the result of a significant reduction in the amount of charcoal stable [ 3H]MBZ-tubulin complexes and was not related to a change in the association constant of the [ 3H]MBZ-tubulin interaction. [ 3H]MBZ binding to tubulin was temperature dependent, reaching maximum levels at 37°C in BZ-S T. colubriformis and 10°C in BZ-R T. colubriformis. Both the BZ-S and BZ-R strains of C. elegans displayed maximum [ 3H]MBZ binding at 4°C. Resistance ratios derived from the amount of [ 3H]MBZ binding in the BZ-S and BZ-R strains and in vitro development assays demonstrated that the temperature dependence and extent of drug binding was indicative of BZ resistance status and was species specific in the BZ-S isolates. These results indicate that biochemical differences exist in the binding of benzimidazole carbamates to tubulin in nematode species, and suggest that the susceptibility of the parasitic nematodes to the benzimidazole anthelmintics is the result of a unique high affinity and/or high capacity interaction ofbenzimidazole carbamates with tubulin.

Distribution, Metabolism, and Elimination of Phenobarbital in Rats: Physiologically Based Pharmacokinetic Model

The distribution, metabolism, and elimination kinetics at two different doses of phenobarbital were examined in rats. After intravenous injection, phenobarbital distributed very rapidly to the liver and kidneys, less rapidly to the muscle and gut, and much more slowly to the brain. At the higher dose, a concentration rebound was observed 1 hr after injection. In addition, phenobarbital distributed unevenly in various organs as a result of a different extent of drug binding. A physiologically based model, including enterohepatic cycling and diffusion resistances between blood and tissue, is proposed for phenobarbital pharmacokinetics. It satisfactorily describes phenobarbital distribution in rats at the two doses and allows an evaluation of fundamental physicobiochemical parameters such as drug-tissue binding constants, blood-tissue transport coefficients, metabolism, and elimination rate constants.

Effect of pulmonary edema on drug transport and binding in rat lung.

The pulmonary absorption and uptake of (35S)phenol red ((35S)PR was measured in anesthetized rats with alpha-naphthylthiourea- (ANTU) induced lung edema. When (35S)PR solution was injected through a tracheal cannula in control animals and the percentage of the tracheal cannula in control animals and the percentage of the dose unabsorbed plotted semilogarithmically against time, an apparent first-order absorption rate was obtained. In contrast, in rats with ANTU-induced edema, the absorption time curve showed at least two different first-order components. Increasing the concentration of (35S)PR from 0.01 to 3 mM resulted in a decrease in the percentage absorption of the compound in controls compared with a relatively constant percentage absorption in edematous lungs. (35S)PR uptake by lung slices from ANTU-treated rats was decreased in the presence of IAA and a N2 atmosphere, and the dye accumulated at a faster rate and to a greater extent than in controls. The results suggest that although energy-dependent drug transport mechanisms remain intact, the porosity of the absorbing membranes and the extent of drug binding in the lung are increased markedly in the presence of edema.

The interaction of phenolic compounds with bacteria. III. Evaluation of the antibacterial activity of hexylresorcinol against Escherichia coli.

Abstract Evaluation of the antibacterial activity of solutions containing hexylresorcinol in the presence and absence of cetomacrogol and sodium chloride is described. The relation between the extent of drug binding, light-scattering changes and the release of cell exudate in E. coli suspensions on addition of hexylresorcinol with the bactericidal activity is examined. Potentiation of the bactericidal activity of hexylresorcinol by sodium chloride and the inactivation by cetomacrogol is discussed with respect to drug binding, light-scattering changes in the bacterial suspensions and the release of bacterial cell exudate in the presence of these agents.

The Interaction of Phenolic Compounds With Bacteria

Abstract The uptake of hexylresorcinol by suspensions of E. coli and the associated release of cellular constituents were examined using heat-killed and butanol-treated organisms. The effect of the addition of cetomacrogol to the system was evaluated in terms of the reduction in the extent of drug binding and the prevention of the hexylresorcinol-dependent light-scattering changes of E. coli suspensions. Sodium chloride potentiation of the latter effect and of the release of cell exudate from the bacteria on treatment with hexylresorcinol was also investigated.