Evaluation of a chronically isolated internal loop in the rat for the study of drug absorption kinetics

A model is described to study absorption kinetics of drugs in the unanesthetized rat. The surgical technique consists of a long-term isolation of an intestinal segment inside the animal. This isolated loop is used in perfusion experiments. In this model the effects of anesthesia and surgical trauma on absorption kinetics are absent. In addition, this model allows for cross-over experimental schemes. Absorption kinetics are evaluated on the basis of steady-state blood levels (Css) of the perfused drug, since the animal can be used in experiments over a long time period. Steady-state blood levels can be used as a measure of the absorption if the compound under investigation shows linear elimination kinetics. Dantrolene sodium was used as a model compound to evaluate this technique. The elimination of dantrolene sodium followed linear kinetics after different intravenous doses in the same rat. The half-life of elimination (t1/2 beta) of dantrolene sodium was approximately 45 min. Perfusions of two different concentrations of dantrolene sodium in the same rat showed that an increase of the perfusate concentration results in a proportional increase in the Css. A prerequisite for performing cross-over experiments is that the absorption characteristics of the isolated segment are constant during the experimental period. This model showed a constant absorption of dantrolene sodium on consecutive days, over a two-week period, in the same rat.