Review Articles
Quantitative Determination of Drug Bioavailability and Biokinetic Behavior from Pharmacological Data for Ophthalmic and Oral Administrations of a Mydriatic Drug

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Abstract

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 a single dose of drug by any route of administration. The results of such analyses permit an evaluation of the physiological availability characteristics of drugs from pharmaceutical dosage forms and the elucidation of the kinetics and mechanisms operative in the passage of drugs across in vivo 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. In the present study, kinetic pharmacological data for tridihexethyl chloride were transformed to obtain the temporal variation of biophasic drug levels, which in turn provided the input for least-squares fits to the linear two- and three-compartment models studied. Digital computer programs, employing an iterative systematized guessing method, were designed to aid in fitting the mathematical models. A triexponential fit was found to be the best with the constraints imposed on the model parameters. The method is further exemplified by its application to the determination of drug absorption following oral and ophthalmic administration.

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      The premise of dose-response-time (DRT) data analysis is that the PD data provide sufficient information to identify a biophase-driven pharmacodynamic (PD) model (Smolen, 1971).

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      This biophase library consists of feasible models derived from the kinetic information in the response-time course in combination with knowledge of the physiology. DRT data analysis dates back to the 1960s and 1970s when Smolen (Smolen and Weigand, 1973; Smolen, 1971; Smolen, 1976) and Levy (Levy, 1964) introduced the concept. Smolen used response data to quantify the bioavailability and biokinetic behaviour of a mydriatic drug after oral and ophthalmic administration whilst Levy derived a relation between the pharmacological effect and elimination rate of a mydriatic drug.

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      The development of DRT has sometimes been held back by the belief that it suffered from several limitations. Thus, Smolen (cf. Smolen, 1971) thought that dose–response–time data analysis might be expected to fail unless linear kinetics, linear dynamics, time-constant parameters pertain, and no active metabolites, tolerance and rebound are involved. However, since then it has been demonstrated that the drug effect can be indirect, display nonlinear kinetics with regard to dose and time, exhibit hysteresis with the drug levels in the biophase and display feedback (cf. Gabrielsson et al., 2000).

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