Utilization of goldfish as a biological model for the estimation of drug permeability

Date

1977

Authors

Cascella, Peter J.

Journal Title

Journal ISSN

Volume Title

Publisher

Abstract

The purpose of this investigation was to examine in detail the possibility of utilizing goldfish as a biological model to predict drug activity and absorption characteristics. In the present investigation a series of derivatives of lidocaine, a local anesthetic agent, were used as the model drug compounds. The unionized form of the drug moiety has been demonstrated to be responsible for the production of the pharmacological endpoints of overturn which is defined as a loss of righting reflex and death in the goldfish and the ability of the goldfish membranes to resist changes in permeability over a pH range of 6-8 has been demonstrated. An apparent trend is shown to exist, in that, as the lipophilicity of the anesthetic agents increase (as reflected by the partition coefficient) so does the absorption rate constant of drug into the fish. An inverse relationship was found to exist between the lipophilicity of the anesthetic agents employed in the study and the apparent minimum effective concentrations (MECs) defined as the concentration of drug in the aqueous solution at or below which no pharmacological response occurs. The significance of the MECs in terms of a meaningful constant in the model are shown to be subject to question. No dramatic change in interpretation of the results utilizing either pharmacological endpoint (overturn or death) was demonstrated for comparison purposes between the anesthetic agents employed in the study in terms of the absorption rate constants or the apparent minimum effective concentrations of the drugs. The ability to predict the time of occurrence of one endpoint (death) from another (overturn) was also demonstrated and the proportionality constant between the two endpoints is suggested to be the ratio of the amount of drug in the fish at the time of the respective endpoints. Comparison of the results obtained from the goldfish with those obtained from experiments utilizing everted rat small intestine reveals a distinct difference between the two models. The ionized form of the drug moiety appears to be capable of crossing the everted rat small intestine at an appreciable rate although not as rapidly as the unionized form of the drug species. No apparent relationship appears to exist between the rate constants for transfer across the everted rat small intestine and the lipophilicity of the compounds employed in the study. The mucosal epithelium was demonstrated to be a non-rate limiting barrier in the transfer of these compounds across the everted rat small intestinal membrane regardless of the magnitude of the anesthetic agents' clearance across the in vitro preparation.

Description

Keywords

Citation