Application of an indwelling vascular access port for intravenous administration in a repeated and intermittent dose toxicity study in rats

Abstract

Totally implantable catheter animal models are considered useful for pharmacological and toxicological studies. In this report, we assessed the feasibility of using an indwelling vascular access port (VAP) in rats for long-term evaluation of repeated and intermittent dose toxicity studies. In Experiment 1, the VAP devices were implanted in male and female rats and a saline solution administered intravenously via the posterior vena cava for 2 weeks (4 ml/kg, 2 ml/min, 5 times/week, 10 times total). General conditions, body weight and blood chemistry showed no toxicological changes compared with the rats in the non-implanted, non-treated group. Hematology changes such as transient increases in peripheral blood reticulocytes and eosinophils were noted post-implantation. In pathology, proliferation of the endothelium at the site of VAP implantation and perivascular inflammatory cell infiltration including eosinophils in lung were noted at the end of the treatment period. Moreover, we found that the lumbar area is more suitable for VAP implantation than the back of neck for young, still growing rats. Experiment 2 included a 1-month intravenous intermittent dose (4 ml/kg, 2 ml/min, 1 time/week, 5 times total) toxicity study in VAP-implanted rats followed by a 1-month recovery period conducted under Good Laboratory Practice (GLP) regulations. The results suggested that an animal model with implanted VAP is useful for intermittent intravenous dosing of drugs. Moreover, VAP implantation in animals is expected to be extrapolated to use VAP in humans in clinical studies.