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Physiological disposition of aerosolized MK-679 in rats
D J Tocco1, F A deluna, E Vadas
1Merck Sharp & Dohme Research Laboratories, West Point, PA 19486.
Abstract:
[14C]MK-679, a potent antagonist of leukotriene D4, was suspended in freon under pressure and sprayed into rat lungs through a tracheal cannula. The particle size of the drug was 1 to 5 microns, and the mean dose was 98.8 +/- 4.46 micrograms/rat. Time course studies indicate that MK-679 was slowly but efficiently absorbed from the lung, with only 6% of the dose remaining in the lung at 6 hr. Biliary excretion, the major route of elimination of aerosolized MK-679, accounted for 48% of the dose in 6 hr. Concentrations of the parent drug plateaued in plasma at 1 to 4 hr, and drug was not detectable in plasma at 6 hr. The parent drug accounted for 94% of the radioactivity in the lung, indicating no significant metabolism by lung tissue. The concentration of MK-679 after aerosol administration was higher in the lung and lower in plasma than after iv administration of the drug at 28 times the aerosol dose. The results of this study suggest that inhalation of MK-679 should be a considered route of administration for the treatment of asthma.
Insights
Inhaled MK-679, a leukotriene D4 antagonist, is efficiently absorbed from rat lungs. This study suggests aerosolized MK-679 may be a viable treatment for asthma.
Area of Science:
- Pharmacology
- Pulmonary Medicine
- Drug Delivery
Background:
- Leukotriene D4 antagonists are crucial in managing asthma.
- Optimizing drug delivery to the lungs is essential for effective asthma treatment.
Purpose of the Study:
- To evaluate the pharmacokinetic profile of aerosolized MK-679 in rat lungs.
- To determine the absorption, distribution, metabolism, and excretion of MK-679 following inhalation.
Main Methods:
- Rats were administered aerosolized [14C]MK-679 (1-5 micron particles) via tracheal cannula.
- Time course studies monitored drug concentrations in lung, plasma, and bile.
- Radioactivity was quantified to assess absorption and excretion.
Main Results:
- MK-679 was slowly but efficiently absorbed from the lungs, with 6% remaining at 6 hours.
- Biliary excretion was the primary elimination route (48% of dose within 6 hours).
- Plasma concentrations plateaued at 1-4 hours and were undetectable by 6 hours; lung tissue showed minimal metabolism.
Conclusions:
- Inhalation of MK-679 results in sustained lung concentrations and efficient absorption.
- Aerosol administration leads to higher lung and lower plasma drug levels compared to intravenous delivery.
- Inhalation of MK-679 is a promising route for asthma treatment.