Abstract

The analog computer is an extraordinary tool for the elucidation of the mechanisms and rates of gastrointestinal absorption into the blood, diffusion into the tissue, and elimination into the urine of a drug. Its use, as developed in these studies, permits the investigation and quantification of distribution and excretion processes for which the application of the methods of analytical mathematics is most approximate and difficult.

The application of these techniques to the interpretation of the pharmacological data on psicofuranine is consistent with the results of analytical mathematics. These methods and equipment permitted the automatic plotting of drug levels in all physiological depots at any time on both intravenous and oral administration.

With respect to psicofuranine, analog computer techniques indicate that:

(a) At least one other additional large vascular space of enhanced permeability may exist in the intact dog which is not present on nephrectomy. The intravenous dosage blood level data are not consistent with the premise of only one vascular space, no matter what permeability and size are hypothesized.

(b) On oral administration the psicofuramne is primarily absorbed from the intestine. The relative absorption of the drug from the stomach to that from the intestine is consistent with a postulated pH 2.2 of the stomach and with the model of nonabsorption of the ionized nucleoside of pK'_a of 3.9.

(c) Appearance of psicofuranine in the urine does not preserve material balance. Agreement occurs when the amounts excreted are plotted as the percentage of the total excreted rather than as the percentage of the dose. This is indicative of some irreversible binding or consumption of drug within the animal.

The kinetic investigations of the acid catalyzed degradations of psicofuranine permitted estimates of in tvivo degradation in the gastrointestinal tract.