Drug-Absorption Analysis from Pharmacological Data I: Method and Confirmation Exemplified for the Mydriatic Drug Tropicamide

A theoretical basis is developed for the performance of drug-absorption analysis from data obtained from the observation of the time course of pharmacological response intensity following single, multiple, or continuous dosing of a drug by any route of administration. The results of such analyses permit an evaluation of the physiological availability characteristics of drugs from dosage forms and the elucidation of the kinetics and mechanisms operative in the passage of drugs across biological barriers. It is demonstrated that through the suitable use of intravenous dose-effect curves, the postulation of hypothetical models for pharmacon-receptor site interaction is obviated. The dose-effect curve graphically provides the relationship between the quantity of drug in body compartments (biophase) and the observed intensity of drug response. The use of pharmacological data in contrast to the use of time course of drug level in body fluid data has the advantage, in addition to not requiring a method of direct assay for the drug, of being applicable to cases where the drug first penetrates from a local site of administration to a vicinal site of action prior to reaching the systemic circulation. The method is confirmed and illustrated for tropic-amide, with results derived from the slow intravenous infusion of the drug to rabbits and the measurement of pupillary diameters. Agreement was observed between the quantities of drug known to be infused at any time and the amounts calculated wholly from pharmacological data on the basis of an assumed single-compartment model. The rapid appearance of the maximum mydriatic response following rapid intravenous dosing allows approximation of the biophase as a compartment kinetically indistinguishable from the central systemic compartment.