Penetration of brodimoprim into human neutrophils and intracellular activity
| Autor: | P.C. Braga, E. Fonti, S. Reggio, S. Maci, M. Dal Sasso, G Bondiolotti |
|---|---|
| Rok vydání: | 1996 |
| Předmět: |
Phagocyte
Antimetabolites Cell Survival Neutrophils Phagocytosis Microbial Sensitivity Tests In Vitro Techniques Trimethoprim Microbiology chemistry.chemical_compound Anti-Infective Agents Pharmacokinetics Extracellular medicine Humans Pharmacology (medical) Chromatography High Pressure Liquid Respiratory Burst Antibacterial agent Pharmacology Chemistry Temperature Hydrogen-Ion Concentration Respiratory burst Kinetics Infectious Diseases medicine.anatomical_structure Brodimoprim Folic Acid Antagonists Intracellular Research Article |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 40:2392-2398 |
| ISSN: | 1098-6596 0066-4804 |
| DOI: | 10.1128/aac.40.10.2392 |
| Popis: | The entry of an antibiotic into phagocytes is a prerequisite for its intracellular bioactivity against susceptible facultative or obligatory intracellular microorganisms. Brodimoprim is a dimethoxybenzylpyrimidine that has recently entered into clinical use, and its uptake into and elimination from human polymorphonuclear neutrophils (PMNs), together with its effects on normal phagocytic and antimicrobial mechanisms, have been investigated. Brodimoprim uptake by PMNs was determined by a velocity-gradient centrifugation technique under various experimental conditions and was expressed as the ratio of the intracellular to the extracellular drug concentration (C/E) in comparison with the C/E of trimethoprim, which was used as a control drug. After incubation with 7.5 micrograms of brodimoprim per ml, PMNs accumulated brodimoprim (C/E, 74.43 +/- 12.35 at 30 min) more avidly than trimethoprim (C/E, 20.97 +/- 6.61 at 30 min). The cellular uptake of brodimoprim was not affected by temperature, 2,4-dinitrophenol, or potassium fluoride and was increased with an increase in the pH of the medium. It was reduced in formaldehyde-killed PMNs. The efflux of brodimoprim was very rapid (46% after 5 min). The liposolubility of brodimoprim was about three times that of trimethoprim, as was the uptake. Therefore, a possible passive transmembrane diffusion mechanism might be proposed. Brodimoprim did not decrease either phagocytosis or phagocyte-mediated bactericidal activity, nor did it affect oxidative burst activity, as investigated by luminol-amplified chemiluminescence. On the basis of the pharmacokinetic data for brodimoprim, the concentration of 7.5 micrograms/ml was chosen as the highest concentration attainable in serum by oral therapy, and at this concentration of brodimoprim, the amount of drug that penetrated into PMNs was able to maintain its antimicrobial activity without interfering with the functions of the PMNs. |
| Databáze: | OpenAIRE |
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