This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Moli1901 is a 19 amino acid polycyclic peptide that may be useful in treating cystic fibrosis. The compound is poorly absorbed in rats after inhalation exposure, and its half-life in lungs of rats is 64 days. A preliminary study suggested that absorption and lung half-life in dogs was similar to that in rats. A more definitive study in dogs is required by the FDA. Because Moli1901 is synthesized by fermentation, production of a sufficient quantity of radiolabeled material to do this study with 14C at doses compatible with liquid scintillation analysis is difficult, time-consuming and expensive. However, the exquisite sensitivity of accelerator mass spectrometry (AMS) should allow the study to be done with material already available. We propose using intratracheal instillation as a surrogate for inhalation exposure to allow better control of material delivered to the lungs. A total of 12 dogs will be given the compound. Groups of three animals will be killed at selected times after the dose for measurement of 14C in tissues. Blood, urine and feces will be collected to determine the systemic pharmacokinetics and elimination of the compound. In addition, selected samples of tissue, urine or plasma will be extracted and fractionated by HPLC to look for Moli1901-related material. This will give an indication of whether the compound is metabolized in dogs. Update: The study was conducted and all AMS data collection and analysis resulted the publication: Rickert DE, Dingley K*, Ubick E*, Dix KJ, Molina L. (2005) Determination of the tissue distribution and excretion by accelerator mass spectrometry of the nonadecapeptide (14)C-Moli1901 in beagle dogs after intratracheal instillation. Chem Biol Interact. Vol 155/1-2 pp 55-
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