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G L Amidon

Publications and source records attributed to G L Amidon.

At least 181 records · Page 10Linked to original sources
PubMed1981

Physicochemical property modification strategies based on enzyme substrate specificities III: carboxypeptidase A hydrolysis of aspirin derivatives.

The aspirin derivatives aspirin phenylalanine and aspirin phenyllactic acid were studied as substrates for carboxypeptidase A. The phenyllactic acid derivative (an ester) was the best substrate but showed considerable product inhibition. The kinetic parameters for both substrates were in the range expected on the basis of other known substrates. The results indicate that the acylamide substituent (drug) has only a small effect on the enzyme kinetic parameters. Consequently, carboxypeptidase A may serve as a reconversion site for many drug derivatives.

Aspirin↗
PubMed1981

On the use of a dynamic approach to the estimation of dissociation constants for reversible competitive antagonists.

A dynamic approach to evaluating reversible competitive antagonists has been used in estimating the dissociation constant (apparent KB) for (+/-)-sotalol at beta adrenergic receptors which mediate a positive chronotropic response in rat atria. Cumulative dose-response curves to the beta agonists (-)-isoproterenol and (-)-soterenol were obtained after mixing each agonist with (+/-)-sotalol at fixed ratios (Q = [antagonist]/[agonist]). Experimental and theoretical dose-response curves obtained with the dynamic approach were in good agreement and the lowered maximum responses to the agonist-antagonist mixtures were dependent on Q. Also, apparent KB values for (+/-)-sotalol determined by three methods were independent of Q and agonist employed in the experiment. Apparent KB values for (+/-)-sotalol obtained by the dynamic method (6 x 10(-7)-2 x 10(-6) M) were similar to those obtained by the traditional equilibrium or static approach. As judged by the similarity of the apparent KB values derived by the two independent theoretical models, the dynamic approach may be considered an effective and alternative means to evaluate reversible competitive antagonists.

Animals↗
PubMed1980

Improving intestinal absorption of water-insoluble compounds: a membrane metabolism strategy.

A strategy for improving the intestinal absorption of water-insoluble drugs was developed and tested. The strategy is based on making a soluble derivative of an insoluble compound which, in turn, is a substrate for enzymes in the surface coat of the brush border region of the microvillous membrane. Consequently, just prior to reaching the membrane, the physical properties of the diffusing species are changed from polar to nonpolar. The experimental test used two drug-drug derivative pairs, estrone-lysine estrone ester and p-nitroaniline-lysine p-nitroanilide. Wall permeabilities were determined using an external perfusion technique in the rat intestine and a laminar flow convective diffusion model for transport in the lumen. Analysis of the permeability results indicates that the derivatives have higher wall permeabilities than the parent compounds and that the microvillous surface coat may be a significant contributor to the intestinal wall resistance. Comparison of the absorption rates for estrone and the lysine estrone ester indicates that the absorption rate of the derivatives could be up to five orders of magnitude greater than that for the parent compound.

Aniline Compounds↗
PubMed1980

Analysis of models for determining intestinal wall permeabilities.

In determining intestinal wall permeabilities, several mass transport models may be applied to analyze the results from external perfusion experiments. The appropriateness of any given model depends on the applicability of the model assumptions to the experimental system. This report compares several mass transport models with respect to their assumptions and applicability to a particular experimental design. The models are shown to differ in their assumptions regarding convection and diffusion in the perfusing fluid. However, since the wall permeability is an unknown parameter in each model and is estimated from the data, all of the models fit the mass transfer results reasonably well, despite fundamentally different assumptions. However, the determined permeabilities differ. Residence time distribution analysis of the experimental system is more sensitive to the model assumptions. It is shown that, in a particular experimental system, laminar flow in a cylindrical tube is the most appropriate model. The model also has the advantage of implicitly accounting for the convection-diffusion problem in the perfusing fluid. Hence, the diffusion layer thickness is not estimated from the data. With the hydrodynamics defined, the relative permeabilities resulting from the application of the several models to the data can be interpreted. The wall permeability determined in the suggested manner provides an estimate of the limiting assistance under perfect mixing conditions.

Animals↗
PubMed1977

Pharmacokinetics of alcohol following single low doses to fasted and nonfasted subjects.

The absorption and elimination characteristics of alcohol have been studied in healthy fasted and nonfasted human volunteers using low single doses. In non-fasted subjects, carbohydrate reduced overall alcohol bioavailability by about 96 percent, compared to 90 per cent for fat and 75 per cent for protein. Inhibition of absorption in nonfasted subjects appeared to be due to less alcohol being available for absorption rather than a reduced absorption rate. Serum alcohol levels in fasted subjects were interpreted in terms of both first-order and zero-order absorption followed by first-order elimination. Of the two proposed models, that utilizing zero-order absorption provided a marginally better fit to observed data.

Adolescent↗
PubMed1976

Comparison of several molecular topological indexes with molecular surface area in aqueous solubility estimation.

The molecular topological indexes proposed by Wiener (Wiener number), Hosoya (Z-value), and Randic (branching index) were corelated with computed molecular surface areas and aqueous solubilities for the monofunctional aliphatic alcohols, ethers, ketones, aldehydes, carboxylic acids, esters, and hydrocarbons. Comparison of the indexes with molecular surface area indicates that all three indexes (or simple modifications) correlate with molecular surface area and, although computed in different manners, reflect molecular topology. Comparison of the correlations of log solubility with the several indexes leads to the following conclusions: (a) the branching index works well for aliphatic, acyclic monofunctional compounds but not cyclic aliphatic compounds; (b) the square root of the Wiener number correlates less satisfactorily with log solubility than the other indexes but more correctly handles cyclic compounds (when generalized after Hosoya); (c) correlations of log solubility with the log Z-value are satisfactory, but the index is difficult to compute; and (d) the molecular surface are represents the single best parameter with which to correlate and estimate aqueous solubility due to its generality. However, for a restricted series of compounds, the branching index is perhaps the most useful index by virtue of its simplicity.

Chemical Phenomena↗
PubMed1976

Solubility of nonelectrolytes in polar solvents IV: nonpolar drugs in mixed solvents.

The molecular and group surface area approach to solubility is shown to be applicable to mixed aqueous solvent systems. An equation is derived which is consistent with the exponential increase in the aqueous solubility of nonpolar drugs that frequently accompanies the addition of a cosolvent. This equation predicts that: (a) the ability of a drug to be solubilized by a cosolvent is proportional to its hydrophobic surface area per molecule, and (b) the ability of a cosolvent to solubilize any drug is inversely proportional to its interfacial tension against a reference liquid hydrocarbon. These predictions are experimentally verified with solubility studies of several alkyl p-aminobenzoates in propylene glycol-water mixtures and of hexyl p-aminobenzoate in mixtures of water the ethanol, methanol, ethylene glycol, propylene glycol, glycerin, and formamide.

Aminobenzoates↗
PubMed1975

Solubility of nonelectrolytes in polar solvents III: Alkyl p-aminobenzoates in polar and mixed solvents.

The relative solubilities of n-alkyl p-aminobenzoates in water, proplyene blycol-water mixtures, proplyene glycol, and several other pharmaceutically important solvents can be predicted on the basis of a theoretical equation. This equation relates the activity coefficient of the hydrophobic portion of the molecule to the product of its surface area and its interfacial tension [free energy per unit area of a hydrocarbon (tetradecane) against the polar or semipolar solvent of interest]. The assumptions, conclusions, and applicability of the theorectical relationship are compared to those of the Scatchard-Hildebrand approach.

Alcohols↗
PubMed1975

Changes in mechanical events and adenosine 3',5'-monophosphate levels induced by enantiomers of isoproterenol in isolated rat atria and uteri.

Beta adrenergic receptors of rat atria and uteri were examined with the use of enantiomers of isoproterenol as agonists and mechanical responses and adenosine 3',5'-monophosphate (cyclic AMP) levels as measured effects. Assuming that stereoselectivity reflects the unique asymmetry of receptors, potency differences between the enantiomers are expected to provide a sensitive indication of ligand binding. All effects in each tissue were investigated under similar experimental conditions. Both isomers produced the same maximum effect on all measured responses. Enantiomeric potency differences (in log units) for positive chronotropic and inotropic responses and increases in cyclic AMP levels in atria were 3.31, 3.51 and 3.48, respectively. In uteri, the values for reduction of spontaneous contractile amplitude and increases in cyclic AMP were 2.90 and 2.79 log units, respectively. Even though these absolute values varied slightly with the experimental conditions, they were consistently smaller in uteri than in atria. In both tissues, dose-response curves for production of mechanical effects were greater than 2 log units to the left of those for increases in cyclic AMP levels. Regardless of the interpretation of this phenomenon, the results show the following. 1) The stereoselectivity for isoproterenol-induced effects is different between the two tissues at both levels of response. Therefore, it is suggested that this reflects dissimilar beta adrenergic receptor types in rat atrium vs. rat uterus. 2) The stereochemical selectivity for isoproterenol-induced mechanical effects and increases in cyclic AMP is the same in rat atrium and in rat uterus. Therefore, the data support the postulate that cyclic AMP is formed from interaction of isoproterenol with a receptor that is similar to the one activated to produce a mechanical effect.

Animals↗