Antimicrobial characterization and interrelationships of dirithromycin and epidirithromycin

Abstract

Dirithromycin is the 9-N,11-O-oxazine adduct formed from 9(S)-erythromycylamine and 2-(2-methoxyethoxy)acetaldehyde in which the methoxyethoxymethyl substituent on the oxazine ring possesses the R configuration. Epidirithromycin is its isomer in which the methoxyethoxymethyl substituent has the opposite (S) configuration. Both compounds readily epimerize in solution, reaching an equilibrium ratio of 85:15 in favor of dirithromycin, given sufficient time. The rate of interconversion is dependent upon pH, temperature, and solvent. An enriched sample of epidirithromycin (95% purity) was synthesized by condensing erythromycylamine and 2-(2-methoxyethoxy)acetaldehyde in diethyl ether as the reaction solvent, and the product was fully characterized by nuclear magnetic resonance spectroscopy and high-pressure liquid chromatographic (HPLC) analysis. Both oxazine derivatives readily hydrolyze to erythromycylamine, so all three compounds exhibit the same antibiotic activity in vitro. In order to determine whether dirithromycin itself possesses significant antimicrobial activity without initial hydrolysis to erythromycylamine, inhibition of cell-free ribosomal protein synthesis was measured under conditions which were adapted to minimize hydrolysis, as measured by analytical HPLC in parallel experiments. Under these particular conditions, inhibition of ribosomal protein synthesis by dirithromycin was <10% of the value measured for erythromycylamine.

Interference of Antibacterial Agents with Phagocyte Functions: Immunomodulation or “Immuno-Fairy Tales”?

“…In particular, Geerdes-Fenge et al (107) have assessed the in vivo uptake of dirithromycin by PMNs from volunteers by measuring erythromycylamine production. These authors used a bioassay, and it is recognized that the antibacterial activity of dirithromycin is less than 10% that of its hydrolysis product, erythromycylamine (179). However, when the uptake of these two drugs was assessed in vitro by a radiolabeling technique, the uptake of dirithromycin was significantly higher than that of its metabolite (265).…”

Interference of Antibacterial Agents with Phagocyte Functions: Immunomodulation or "Immuno-Fairy Tales"?

“…In particular, Geerdes-Fenge et al (107) have assessed the in vivo uptake of dirithromycin by PMNs from volunteers by measuring erythromycylamine production. These authors used a bioassay, and it is recognized that the antibacterial activity of dirithromycin is less than 10% that of its hydrolysis product, erythromycylamine (179). However, when the uptake of these two drugs was assessed in vitro by a radiolabeling technique, the uptake of dirithromycin was significantly higher than that of its metabolite (265).…”

Impurity Profiling of Dirithromycin by Liquid Chromatography Coupled to Electrospray Ionization Mass Spectrometry

“…Several related substances of dirithromycin have already been characterized (Diana, Manyanga, et al 2006;Counter et al 1991;Duran et al 2004;Diana, Govaerts, et al 2006;Firl et al 1990;Kirst et al 1995;Luger and Maier 1979). An overview of the already known and newly characterized compounds is given in Table 1, together with their relative content (%).…”

“…Other potential impurities are erythromycin B hydrazone, erythromycylamine B and C (Diana, Govaerts, et al 2006). Acidic solutions accelerate the formation of epi-dirithromycin (Duran et al 2004;Firl et al 1990;Kirst et al 1995).…”