Pulmonary Pharmacokinetics of Tulatuthromycin in Mice and Pigs

Tulathromycin is an antimicrobial approved for use in the treatment and control of bovine respiratory disease and treatment of swine respiratory disease in United States and European Union. This macrolide is a unique drug which has an extraordinary capacity to accumulate in lung tissue and shows distinctive pharmacokinetic features in animals. The pulmonary pharmacokinetics of tulathromycin in mice and pigs were evaluated in this dissertation. In mice, the pulmonary pharmacokinetics of tulathromycin was evaluated in healthy animals and animals challenged with lipopolysaccharide of Escherichia coli (LPS-Ec). A group of challenged animals were also rendered neutropenic. In pigs, the pulmonary pharmacokinetics of tulathromycin was assessed in healthy animals and animals challenged intra-tracheally with LPS-Ec. The pulmonary pharmacokinetics of tulathromycin was assessed using lung tissue (middle and caudal lobes), pulmonary and bronchial epithelial lining fluid (BELF) samples. We introduce a novel technique for the assessment of the concentration vs. time profile of tulathromycin in BELF. This technique is based in the use of fiberscopically guided bronchial micro-sampling probes (BMSp). The BMSp were first evaluated in a pilot trial. Then, the BMSp were used as sampling tool for harvesting BELF in a larger study. The use of BMSp represents a cost effective technique. This technique can be introduced in discovery and preclinical pharmacokinetics studies for screening of candidate drugs that will be indicated for the treatment of respiratory conditions. This technique might enhance the experimental design and maximize the experimental resources (number of animals, time, and cost). This dissertation expands the understanding about the distribution of tulathromycin into the lungs. It evaluates the kinetics of tulathromycin in middle and caudal lobes and intra-airways compartment from healthy and animals with an acute pulmonary inflammatory response. This work provides the first evidence of the pharmacokinetics of tulathromycin in lung tissue administered to neutropenic, normopenic, and neutrophilic mice. Finally, this dissertation introduces and evaluates an innovative technique for the study of pulmonary pharmacokinetics of drugs in veterinary species.