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Interactions between HMR 3647, a new ketolide, and human polymorphonuclear neutrophils
D Vazifeh1, A Preira, A Bryskier
1INSERM U 479, Laboratoire d'Hématologie et Immunologie, CHU X. Bichat, 75018 Paris, France.
Antimicrobial Agents and Chemotherapy
|August 4, 1998
Summary
The new ketolide HMR 3647 concentrates effectively within human polymorphonuclear neutrophils (PMNs), impacting their functions. This study explores its unique pharmacokinetic properties and effects on PMN activity.
Area of Science:
- Pharmacology
- Microbiology
- Immunology
Background:
- Ketolides are a class of antibiotics active against intracellular pathogens.
- Previous research showed high concentration of ketolide HMR 3004 in human polymorphonuclear neutrophils (PMNs).
- The structural difference in HMR 3647 (3-keto group instead of L-cladinose) may alter its pharmacokinetic properties compared to erythromycin A derivatives.
Purpose of the Study:
- To evaluate the cellular accumulation and efflux of the novel ketolide HMR 3647 in human PMNs.
- To investigate the impact of HMR 3647 intracellular accumulation on PMN functions, specifically degranulation and superoxide anion production.
Main Methods:
- Radiolabeled HMR 3647 was used to determine uptake kinetics in PMNs via velocity gradient centrifugation.
- Cellular concentration, localization (granular compartment vs. membranes), and efflux were measured.
- The effects of temperature, extracellular pH, extracellular Ca2+, and verapamil on uptake were assessed. PMN functions (granule exocytosis, superoxide anion production) were measured following HMR 3647 exposure.
Main Results:
- HMR 3647 was avidly concentrated by PMNs, reaching high cellular-to-extracellular ratios (up to 348:1) without saturation within 3 hours.
- The drug primarily localized to the granular compartment (approx. 60%) and showed gradual efflux from loaded cells.
- Uptake exhibited Michaelis-Menten kinetics, was temperature-dependent, required extracellular Ca2+, and was influenced by verapamil, suggesting efflux stimulation.
- HMR 3647 weakly triggered PMN degranulation but inhibited superoxide anion production in a time- and concentration-dependent manner.
Conclusions:
- HMR 3647 demonstrates significant intracellular accumulation in PMNs, suggesting favorable pharmacokinetics for treating intracellular infections.
- The ketolide's impact on PMN function involves inhibition of superoxide anion production, a key inflammatory response.
- The distinct pharmacokinetic profile and functional effects of HMR 3647 warrant further investigation for its therapeutic potential.