Structural identification of bitespiramycin metabolites in rat: A single oral dose study

Abstract

Bitespiramycin is a macrolide antibiotic consisting of a mixture of some nine spiramycin ester derivatives. It has a similar spectrum of antibiotic activity to that of spiramycin but has superior pharmacokinetic properties. In this study, a rapid and facile LC/ESI-MSn method was applied to study the metabolism of bitespiramycin in rat following a single oral dose (80 mg kg-1). Concentrations of parent drug constituents and metabolites were determined in plasma, urine, feces and bile. Concentrations of parent drug constituents and metabolites in plasma were very low. In urine, feces and bile, parent drug constituents and 38 metabolites were identified on the basis of their chromatographic and mass spectrometric properties. The identity of 17 metabolites was confirmed by comparison with reference substances. The principal metabolites were the corresponding spiramycins formed by hydrolysis of the 4''-(3-methylbutanoate) groups. Other important metabolic pathways were: hydrolytic loss of the forosamine and mycarose sugars; aldehyde reduction; cysteine conjugation of the aldehyde group; and hydrolysis of the lactone ring. Products formed by lactone ring opening were found only in urine, and those formed by aldehyde reduction were found only in feces. Aldehyde reduction and hydrolytic loss of forosamine represent novel biotransformation pathways for spiramycin derivatives.

Significant Reduction of Brain Cysts Caused by Toxoplasma gondii after Treatment with Spiramycin Coadministered with Metronidazole in a Mouse Model of Chronic Toxoplasmosis

“…Spiramycin has an oral bioavailability of ca. 35%, demonstrates low plasma protein binding (20%; which may explain the extensive tissue penetration), and is associated with hepatic to active metabolites (32). The elimination half-life (t 1/2 ) is around 6 to 8 h; spiramycin is excreted in bile and breast milk (13), and ca.…”

Characterization of impurities in spiramycin by liquid chromatography/ion trap mass spectrometry

“…All the other spectral data were consistent with the identification of UNK1 and UNK12 as deforosaminylspiramycin I and deforosaminylspiramycin III, respectively. These two compounds correspond to the metabolites of bitespiramycin found in rat after a single oral dose 22…”

“…Based on the results from these two publications,19, 20 it can be concluded that the fragmentation pathways of singly and doubly charged ions are in accordance. Degradation of spiramycins in acidic conditions and metabolism in rat and pig liver were also studied 17, 22, 23. In acidic conditions, SPM III produced two degradation products with m/z 755 (NSPM I) and 614 (forosidin III).…”

Separation and purification of bitespiramycin by counter-current extraction

“…Bitespiramycin, a mixture of 4''-O-acylated spiramycin with 4''-O-isovalerylspiramycin as the major components [1], belongs to 16-membered ring macrolide antibiotic [2] used to treat gram-positive bacteria infectious diseases in upper respiratory tract and urinary system [3][4][5].…”