Determination of the tissue distribution and excretion by accelerator mass spectrometry of the nonadecapeptide 14C-Moli1901 in beagle dogs after intratracheal instillation.
Moli1901 is a 19 residue polycyclic peptide antibiotic which increases chloride transport and water mobilization in airway epithelium. These properties suggest that it may be a useful treatment for cystic fibrosis (CF). In this study, we used accelerator mass spectrometry (AMS) to quantify Moli1901 following administration of only 0.045 microCi of 14C-Moli1901 per dog. Limits of quantitation of AMS were 0.03 (urine) to 0.3 (feces) ng equiv. Moli1901/g. Administration of 14C-Moli1901 by intratracheal instillation (approximately 100 microg) into the left cranial lobe of the lung of beagle dogs resulted in retention of 64% of the dose in the left cranial lobe for up to 28 days. Whole blood and plasma concentrations of 14C were <5 ng/ml at all times after the dose. Concentrations of 14C in whole blood and plasma declined over the first day after the dose and rose thereafter, with the rise in plasma concentrations lagging behind those in whole blood. During the first 3 days after the dose, plasma accounted for the majority of 14C in whole blood, but after that time, plasma accounted for only 25-30% of the 14C in whole blood. Tissue (left and right caudal lung lobe, liver, kidney, spleen, brain) and bile concentrations were low, always less than 0.25% the concentrations found in the left cranial lung lobe. Approximately 13% of the dose was eliminated in urine and feces in 28 days, with fecal elimination accounting for about 10% of the dose. The data presented here are consistent with that obtained in other species. Moli1901 is slowly absorbed and excreted from the lung, and it does not accumulate in other tissues. Moli1901 is currently in the clinic and has proven to be safe in single dose studies in human volunteers and cystic fibrosis patients by the inhalation route. No information on the disposition of the compound in humans is available. This study in dogs demonstrates the feasibility of obtaining that information using 14C-Moli1901 and AMS.
Rickert
D E
DE
Lawrence Livermore National Laboratory, Livermore, CA 94550, USA.
Dingley
K
K
Ubick
E
E
Dix
K J
KJ
Molina
L
L
D000818:Animals; D002250:Carbon Radioisotopes; D003550:Cystic Fibrosis / Q000188:drug therapy; D004285:Dogs; D007442:Intubation, Intratracheal; D008168:Lung / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry / Q000295:instrumentation / Q000379:methods*; D010315:Particle Accelerators; D010456:Peptides, Cyclic / Q000493:pharmacokinetics* / Q000652:urine*
D002250:Carbon Radioisotopes; C477246:Moli1901; D010456:Peptides, Cyclic