Cellular accumulation of the new ketolide RU 64004 by human neutrophils: comparison with that of azithromycin and roxithromycin - PubMed (original) (raw)

Comparative Study

Cellular accumulation of the new ketolide RU 64004 by human neutrophils: comparison with that of azithromycin and roxithromycin

D Vazifeh et al. Antimicrob Agents Chemother. 1997 Oct.

Abstract

We analyzed the uptake of RU 64004 by human neutrophils (polymorphonuclear leukocytes [PMNs]) relative to those of azithromycin and roxithromycin. RU 64004 was strongly and rapidly accumulated by PMNs, with a cellular concentration/extracellular concentration ratio (C/E) of greater than 200 in the first 5 min, and this was followed by a plateau at 120 to 180 min, with a C/E of 461 +/- 14.8 (10 experiments) at 180 min. RU 64004 uptake was moderately sensitive to external pH, and activation energy was also moderate (63 +/- 3.8 kJ/mol). RU 64004 was mainly located in PMN granules (about 70%) and egressed slowly from loaded cells, owing to avid reuptake. The possibility that PMN uptake of RU 64004 and other macrolides occurs through a carrier-mediated system was suggested by three key results. First, there existed a strong interindividual variability in uptake kinetics, suggesting variability in the numbers or activity of a transport protein. Second, macrolide uptake displayed saturation kinetics characteristic of that of a carrier-mediated transport system: RU 64004 had the highest Vmax value (3,846 ng/2.5 x 10(6) PMNs/5 min) and the lowest Km value (about 28 microM), indicating a high affinity for the transporter. Third, as observed previously with other erythromycin A derivatives, Ni2+ (a blocker of the Na+/Ca2+ exchanger which mediates Ca2+ influx in resting neutrophils) impaired RU 64004 uptake by PMNs, with a 50% inhibitory concentration of about 3.5 mM. In addition, we found that an active process is also involved in macrolide efflux, because verapamil significantly potentiated the release of all three macrolides tested. This effect of verapamil does not seem to be related to an inhibition of Ca2+ influx, because neither EGTA [ethylene glycol-bis (beta-aminoethyl ether)-N,N',N'-tetraacetic acid] nor Ni2+ modified macrolide efflux. The nature and characteristics of the entry- and efflux-mediating carrier systems are under investigation.

PubMed Disclaimer

Similar articles

• Interaction of the new ketolide ABT-773 (cethromycin) with human polymorphonuclear neutrophils and the phagocytic cell line PLB-985 in vitro.
  Labro MT, Abdelghaffar H, Babin-Chevaye C. Labro MT, et al. Antimicrob Agents Chemother. 2004 Apr;48(4):1096-104. doi: 10.1128/AAC.48.4.1096-1104.2004. Antimicrob Agents Chemother. 2004. PMID: 15047507 Free PMC article.
• Role of extracellular calcium in in vitro uptake and intraphagocytic location of macrolides.
  Mtairag EM, Abdelghaffar H, Douhet C, Labro MT. Mtairag EM, et al. Antimicrob Agents Chemother. 1995 Aug;39(8):1676-82. doi: 10.1128/AAC.39.8.1676. Antimicrob Agents Chemother. 1995. PMID: 7486899 Free PMC article.
• Interactions between HMR 3647, a new ketolide, and human polymorphonuclear neutrophils.
  Vazifeh D, Preira A, Bryskier A, Labro MT. Vazifeh D, et al. Antimicrob Agents Chemother. 1998 Aug;42(8):1944-51. doi: 10.1128/AAC.42.8.1944. Antimicrob Agents Chemother. 1998. PMID: 9687388 Free PMC article.
• Review of macrolides and ketolides: focus on respiratory tract infections.
  Zhanel GG, Dueck M, Hoban DJ, Vercaigne LM, Embil JM, Gin AS, Karlowsky JA. Zhanel GG, et al. Drugs. 2001;61(4):443-98. doi: 10.2165/00003495-200161040-00003. Drugs. 2001. PMID: 11324679 Review.
• The macrolide antibiotics: a pharmacokinetic and pharmacodynamic overview.
  Jain R, Danziger LH. Jain R, et al. Curr Pharm Des. 2004;10(25):3045-53. doi: 10.2174/1381612043383322. Curr Pharm Des. 2004. PMID: 15544496 Review.

Cited by

• Neutrophil-mediated delivery of the combination of colistin and azithromycin for the treatment of bacterial infection.
  Gao J, Hu X, Xu C, Guo M, Li S, Yang F, Pan X, Zhou F, Jin Y, Bai F, Cheng Z, Wu Z, Chen S, Huang X, Wu W. Gao J, et al. iScience. 2022 Aug 30;25(9):105035. doi: 10.1016/j.isci.2022.105035. eCollection 2022 Sep 16. iScience. 2022. PMID: 36117992 Free PMC article.
• Antibiotics in malaria therapy: which antibiotics except tetracyclines and macrolides may be used against malaria?
  Gaillard T, Madamet M, Tsombeng FF, Dormoi J, Pradines B. Gaillard T, et al. Malar J. 2016 Nov 15;15(1):556. doi: 10.1186/s12936-016-1613-y. Malar J. 2016. PMID: 27846898 Free PMC article. Review.
• Ketolide agents HMR 3004 and HMR 3647 (telithromycin) inhibit the growth of Plasmodium falciparum in vitro.
  Makgatho M, Maimela E, Mbajiorgu F. Makgatho M, et al. Afr Health Sci. 2015 Dec;15(4):1271-6. doi: 10.4314/ahs.v15i4.28. Afr Health Sci. 2015. PMID: 26958030 Free PMC article.
• Azithromycin inhibits IL-1 secretion and non-canonical inflammasome activation.
  Gualdoni GA, Lingscheid T, Schmetterer KG, Hennig A, Steinberger P, Zlabinger GJ. Gualdoni GA, et al. Sci Rep. 2015 Jul 8;5:12016. doi: 10.1038/srep12016. Sci Rep. 2015. PMID: 26152605 Free PMC article.
• Azithromycin enhances phagocytic killing of Aggregatibacter actinomycetemcomitans Y4 by human neutrophils.
  Lai PC, Schibler MR, Walters JD. Lai PC, et al. J Periodontol. 2015 Jan;86(1):155-61. doi: 10.1902/jop.2014.140183. J Periodontol. 2015. PMID: 25186779 Free PMC article.

References

1. 1. Am J Cardiol. 1980 Dec 1;46(6):1047-58 - PubMed
2. 1. Antimicrob Agents Chemother. 1992 Jun;36(6):1302-9 - PubMed
3. 1. J Chemother. 1995 Jun;7(3):184-8 - PubMed
4. 1. Blood. 1994 May 1;83(9):2451-8 - PubMed
5. 1. Arzneimittelforschung. 1990 Jun;40(6):686-9 - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources

• Full Text Sources

  • Atypon
  • Europe PubMed Central
  • PubMed Central

• Other Literature Sources

  • The Lens - Patent Citations

• Medical

  • MedlinePlus Health Information

• Miscellaneous

  • NCI CPTAC Assay Portal