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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.

A mass transfer model was developed to describe the dissolution and reaction of acidic and basic compounds from a rotating disk in unbuffered water. Dissolution of two carboxylic acids, 2-naphthoic acid (1) and naproxen [(+)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid, 2], and the free base, papaverine (6,7-dimethoxy-1-veratrylisoquinoline, 3), in aqueous solutions (mu = 0.1 with KCI) at 25 degrees C were investigated. An automated dissolution apparatus, which consisted of microcomputer-controlled autoburets, was constructed to monitor and adjust the pH of the aqueous solutions during the experiments. Unique features of the mass transfer model include treatment of mass transfer as a convective diffusion process rather than a stagnant film diffusion only process; treatment of ionization and acid-base reactions as heterogeneous reactions; use of experimental diffusion coefficients for all species, particularly H+ and OH-; and application of boundary conditions that specify flux for surface ionization produced species. The model accurately predicted the dissolution rate assuming the solubility, pKa, and diffusion coefficient of the compound were independently known. The model also predicted pH at the solid-liquid surface, the flux of H+ from the surface, and the contribution of A- to the total acid flux as a function of bulk pH of the aqueous solution.

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.

The rates of water sorption as a function of relative humidity for water-soluble substances exhibiting deliquescence have been measured in an atmosphere of pure water vapor. The substances studied included a series of alkali halides, choline halides, and sugars. The results were compared with a theoretical model, previously described, which relates the rate of water uptake to the transport of heat produced during the process away from the surface. Taking into account the heat of water vapor condensation, heat of solution, and heat of hydration, when hydration occurs, the model allows excellent a priori prediction of water uptake rates as a function of relative humidity.

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.

Gastrointestinal pH as a function of time was recorded for 4 beagle dogs and 10 human subjects using radiotelemetric pH measuring equipment. Results indicated that in the quiescent phase, gastric pH in the dogs (mean = 1.8 +/- 0.07 SEM) was significantly (p less than 0.05) higher than in humans (1.1 +/- 0.15). No significant difference in the time for the pH monitoring device to empty from the stomach was noted for the two species (99.8 +/- 27.2 min for dogs, 59.7 +/- 14.8 min for humans, p greater than 0.05). The fasting intestinal pH in dogs was consistently higher than in humans, with an average canine intestinal pH of 7.3 +/- 0.09 versus 6.0 +/- 0.14 for humans. The implication of these observations for extrapolation of drug absorption data from dogs to humans are discussed.

The beta-lactam antibiotic oral absorption pathway is studied using a single-pass perfusion technique in the rat small intestine. Beta-lactam antibiotic absorption in the presence of amino acids, small peptides, and other beta-lactams is modeled using a simple competitive inhibition boundary condition at the intestinal wall, with a corrected value for the intestinal wall concentration, Cw, derived from the modified boundary layer analysis. The model-predicted permeability in the presence of an inhibitor is used to characterize the beta-lactam antibiotic intestinal carrier system. Several concentrations of cephalexin, coperfused with a constant concentration of cefadroxil (equal to its Km), showed that the Km of cephalexin approximately doubled from 7.2 (+/- 1.1) to 18.8 (+/- 4.1) mM; Jmax remained unchanged at 9.2 (+/- 1.2) and 11.1 (+/- 2.1) mM; and the carrier permeability, Pc, was reduced by approximately 50% from 1.11 (+/- 0.10) to 0.59 (+/- 0.04), consistent with competitive absorption kinetics. The predicted in situ wall permeability, the mean value of P*w, of beta-lactams perfused in the presence of other beta-lactams was calculated and then compared with experimentally determined values. For cefadroxil, P*w = 0.27 (+/- 0.04), the mean value of P*w = 0.29; for cefatrizine, P*w = 0.67 (+/- 0.09), the mean value of P*w (+/- 0.09), the mean value of P*w = 0.59; and for cephalexin, P*w = 0.56 (+/- 0.05), the mean value of P*w = 0.59.(ABSTRACT TRUNCATED AT 250 WORDS)

As an extension of the model of heat transport control developed for the kinetics of water sorption by water-soluble substances from an atmosphere of pure water vapor, equations have been developed to account for limitations of diffusion on mass transport of water vapor when air is present. Although the inability to determine the vapor diffusion layer thickness prevents using these equations to predict sorption behavior a priori, minimum water sorption rates can be calculated by assuming a diffusion layer thickness equal to the sample chamber radius. Combining heat transport and mass transport produces equations which describe very well the observed sorption by three water-soluble salts in one atmosphere of air. As in the absence of air, sorption rates are predicted and observed to be constant at a given atmospheric relative humidity.

Previous studies suggested that the food-containing canine stomach retains large, nondigestible spheres until all food has emptied; but it is not known whether there is a threshold size or a gradation of sizes that will empty along with food. Further, nothing is known of the effects of such parameters as density, shape, and surface energy on the emptying of nondigestible particles of any given size. To answer these questions 6 dogs with chronic duodenal fistulas were studied. Radiolabeled food and spheres were collected from the fistulas to compare the rate of gastric emptying of the spheres with that of the food. After a standard test meal of 99mTc-labeled liver, steak, and water, diverted chyme was collected over a stack of sieves in 30-min fractions over 5 postcibal hours. The percent of fed spheres and fed 99mTc-labeled liver in each collection was counted, and liquid chyme was returned to the distal duodenum. Spheres with a density of 1 emptied progressively faster as sphere diameters were decreased from 5 to 1 mm; but 0.015-mm spheres emptied at about the same rate as those with diameters of 1 mm. Emptying of the spheres became similar to emptying of the 99mTc-labeled liver at about 1.6 mm. Spheres with densities less than 1 or greater than 1 emptied more slowly than spheres of the same size with a density of 1, whereas paper squares emptied the same way as spheres of comparable size and density. Surface energy did not affect emptying. The findings indicated that both sphere size and density affect their emptying in the presence of food.

The reduced 3-suffix solubility equation (R3SSE) is applied to the characterization of solubility in the ethanol-water system. The data needed are the solubility of the compound in each of the pure solvents and at one ethanol-water composition. This composition has been estimated from solubility data to be 0.56 volume fraction of ethanol. The solubility obtained at this volume fraction is used to estimate the ternary solute-solvent interaction constant, C2. The R3SSE, with the C2 thus obtained, predicts the mixed solvent solubilities of the compounds tested, as accurately as that obtained from several volume fractions. The superiority of the R3SSE over two related equations--a simple second-degree polynomial equation and a simplified form of the R3SSE which neglects contributions to solubility from the solvent mixture--is also demonstrated for a number of solutes.

The primary objective of this study was to define the pH conditions under which supplemental pancreatic enzyme preparations must function in the upper gastrointestinal tract. The hypothesis was that normal or greater acid output in patients with cystic fibrosis (CF), combined with low pancreatic bicarbonate output, results in an acidic duodenal pH, compromising both dosage-form performance and enzyme activity. Gastrointestinal pH profiles were obtained in 10 CF and 10 healthy volunteers under fasting and postprandial conditions. A radiotelemetric monitoring method, the Heidelberg capsule, was used to continuously monitor pH. Postprandial duodenal pH was lower in CF than in healthy subjects, especially in the first postprandial hour (mean time greater than pH 6 was 5 min in CF, 11 min in healthy subjects, P less than 0.05). Based on the dissolution pH profiles of current enteric-coated pancreatic enzyme products, the duodenal postprandial pH in CF subjects may be too acidic to permit rapid dissolution of current enteric-coated dosage forms. However, the pH was above 4 more than 90% of the time on the average, suggesting that irreversible lipase inactivation in the duodenum is not likely to be a significant limitation to enzyme efficacy. Overall results suggest that slow dissolution of pH-sensitive coatings, rather than enzyme inactivation, may contribute to the failure of enteric-coated enzyme supplements to normalize fat absorption.

The boundary layer approach to analyzing the results of the perfused intestinal segment method of measuring membrane permeabilities is applied to the amino acids; leucine, valine, phenylalanine, lysine and aspartic acid and the beta-lactam antibiotics, cephalexin and penicillin V. The analysis indicates that in determining the membrane parameters, Pw vs. Cw data are preferable to using Jss = PwCw vs. Cw data. It is further shown that the carrier permeability, Pc* = Jmax*/Km, may be the most significant parameter to consider since luminal amino acid or drug concentration may generally be below the Km value. A comparison of P*c values for the beta-lactams with results for passively absorbed compounds indicates that the cephalosporins would be expected to be well absorbed orally based on the perfusion results. This suggests that this approach may be useful in estimating oral drug absorption for compounds that are absorbed passively as well as by a carrier-mediated mechanism.