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Published on: December 24, 2016
Pharmacokinetics and tissue distribution of the nonadecapeptide Moli1901 in rats and mice
M J McNulty1, R H Hutabarat, J W A Findlay
1GlaxoSmithKline, Inc., Research Triangle Park, NC 27709, USA.
Abstract:
1. Administration of aerosolized, radiolabelled Moli1901 (duramycin, 2622U90), a 19 amino acid polycyclic peptide, to rats resulted in the deposition of high amounts of radiolabel in the respiratory tract, with deposited radiolabel persisting almost unchanged through 7 days after dosing. Little to no radiolabel was present in the bloodstream of these rats. 2. Rats absorbed little radiolabel after p.o. administration, with nearly all of the dose excreted in the faeces by 2 days after dosing. 3. At 7 days following an intravenous dose, rats excreted 54% of the radiolabel in faeces and 5.4% in the urine, with 44% remaining in the carcass, primarily in the liver (33%). 4. Following an intratracheal instillation dose to rats, radiolabel was eliminated from the pulmonary system with a half-life of 64 days. Excretion was almost exclusively via faeces, with an elimination half-life of 52 days. Plasma and blood concentrations in these animals were uniformly <1 ng eq. ml(-1) at all sampling times. 5. Results in mice given intravenous and oral doses were consistent with those observed in rats. 6. Prolonged retention of Moli1901 in pulmonary tissue supports its use in the treatment of respiratory diseases.
Insights
Moli1901 (duramycin) demonstrated significant deposition and prolonged retention in the respiratory tract following aerosol administration in rats. This suggests potential for treating respiratory diseases due to its pulmonary persistence.
Area of Science:
- Pharmacokinetics
- Drug Delivery
- Respiratory Medicine
Background:
- Moli1901 (duramycin) is a 19 amino acid polycyclic peptide.
- Understanding the pharmacokinetic profile of Moli1901 is crucial for its therapeutic development.
Purpose of the Study:
- To evaluate the disposition and pharmacokinetic profile of radiolabeled Moli1901 in rats and mice.
- To assess the potential of Moli1901 for treating respiratory diseases.
Main Methods:
- Administration of aerosolized, radiolabeled Moli1901 to rats.
- Oral and intravenous administration of radiolabeled Moli1901 to rats and mice.
- Quantification of radiolabel in various tissues, blood, urine, and feces over time.
Main Results:
- Aerosolized Moli1901 showed high deposition and prolonged retention (half-life of 64 days) in the rat respiratory tract with minimal systemic absorption.
- Oral administration resulted in low absorption and rapid fecal excretion.
- Intravenous administration led to significant carcass retention (44%), primarily in the liver, with elimination via feces and urine.
- Plasma concentrations remained very low across all administration routes and species.
Conclusions:
- Prolonged retention of Moli1901 in pulmonary tissue supports its potential utility in treating respiratory diseases.
- The pharmacokinetic profile suggests targeted delivery and sustained release in the lungs.
- Further investigation into Moli1901's efficacy for respiratory conditions is warranted.
