Pirlimycin sulfoxide

Metabolism studies (116) in dairy cows treated twice at a 24 h interval with radiolabeled pirlimycin into all quarters at 200 mg/quarter by the intramammary route showed that the drug was readily absorbed from the udder about 68% of the dose was excreted in the milk, urine, and feces as parent pirlimycin. About 4% appeared as pirlimycin sulfoxide generated by hepatic oxidation, and... 

Reference standards. Pirlimycin was obtained as an Upjohn Control Reference Standard of purity >99% as the hydrochloride hydrate. Pirlimycin sulfoxide was prepared from the treatment of pirlimycin with hydrogen peroxide followed by recrystallization. Samples of pirlimycin adenylate and pirlimycin sulfoxide adenylate were prepared by the procedures described by Argoudelis et al (6). 

Metabolite Profiles in Liver. The total radioactive residue in all 12 livers was efficiently extracted with a mixture of formic, trifluoroacetic, and hydrochloric acids. After neutralization of the acids with ammonium hydroxide and partial purification by solid phase extraction techniques, HPLC/RAM analysis produced essentially a two-component profile. The minor component was pirlimycin itself in relative amounts of 27.6% 9.7%. The bulk of the residue, 77%, was a single substance and was identified by co-chromatography with an authentic standard and by FAB/MS as pirlimycin sulfoxide (PS). The microbiological analysis of the extracts confirmed this relative ratio since PS has an antibiotic activity 142 times less than that of pirlimycin against M.luteus. The ratio of pirlimycin to total residue was therefore established and will provide the necessary correlation of residue depletion needed for the calculation of residue marker concentration (Rm) and the establishment of a tissue withdrawal period. 

Proton Pirlimycin Pirlimycin Sulfoxide P-Adenylate Metabolite Ml PSAdenylate Metabolite M3... 

A complete characterization of the absorption, distribution, metabolism and excretion of pirlimycin in the dairy cow following intramammary administration has demonstrated that pirlimycin is readily absorbed from the udder and excreted largely unchanged in milk and urine. Oxidation of the sulfide to the sulfoxide was the only hepatic metabolism observed. However, microflora in the GI Tract of the cow converted both pirlimycin and pirlimycin sulfoxide to ribonucleotide adducts with the addition on the C-3 hydroxyl of the sugar ring. Elimination kinetics of the pirlimycin residue in milk led to a proposed milk discard time of 36 hours for the US market. 

The lincosamides can undergo extensive transformation by metabolism. For example, in pigs the presence of 26 metabolites was indicated in liver. " Lincomycin sulfoxide, A-demethyllincomycin, and A-demethyllincomycin sulfoxide were all identified in poultry liver. In bovines, pirlimycin sulfoxide and sulfone have been identified as metabolites. In liver and kidney the major residue is the sulfoxide for both lincomycin and pirlimycin, accounting... 

Both pirlimycin and its sulfoxide metabolite were partially converted to ribonucleotide adducts by gastrointestinal tract microflora and excreted in feces. Such adducts have been well documented as products of antibiotic inactivation by bacteria for a variety of substances including lincomycin and clindamycin (117-119). 

In liver, a minor component of total residues was attributed to pirlimycin itself while the bulk, 77%, was attributed to the sulfoxide metabolite (116). The liver contained relatively higher concentrations of total pirlimycin residues than other tissues, the sulfoxide metabolite accounting for approximately 62% of the total residues. 

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