Difference in Exposure and Tolerability when Comparing Intratracheal Instillation with Inhaled Delivery

PURPOSE: To investigate the impact of two different routes of administration on the lung and systemic exposure of drugs designed for local delivery to the lung. METHODS: In our comparative studies, similar lung doses of three different drugs were administered to rodents by both intratracheal instillation and inhaled delivery. RESULTS: An obvious but unexpected difference in the exposure was observed. Immediately after the dose, the initial plasma concentration was much higher whereas the initial fraction of the lung dose in the lung was clearly lower for the instillation compared with the inhaled delivery. There was also a difference in the tolerability for one of the drugs when the same lung dose was administered and the inhaled dose was, in contrast to the instilled dose, tolerated by the mice. CONCLUSIONS: A plausible explanation for the observed but contrary to expected difference is that the drugs leaked from the lung into the systemic circulation already during the instillation procedure due to its invasive nature.