Pirlimycin, metabolism

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... 

RE Hornish, RD Roof, JR Wiest. Pirlimycin residue in bovine liver—a case of reverse metabolism. Analyst 123 2463-2467, 1998. 

A comparative metabolism study in the rat was also conducted to address its relevancy as a toxicological test species. The residue concentration decline kinetics were also determined for pirlimycin in milk from cows treated at a dose rate of 50 mg per quarter in all 4 quarters to establish a milk discard interval for the proposed use. 

Comparative metabolism in the rat. Adult male (6) and female (6) Sprague-Dawley rats were housed individually in polycarbonate metabolism cages and were orally administered by gavage an aqueous solution of " C-pirlimycin HCl. Five daily doses of 29 mg/kg/day were administered at 24-hour intervals to each rat. Urine and feces were collected at 24-hour intervals just before dose administration. The animals were sacrificed at 2 to 3 hours post-last-dose and liver, kidneys, and samples of flank muscle and abdominal fat carefully excised and placed into tared bottles. Homogenates of 2 1 water tissue were prepared for combustion/LSC analysis. Metabolite profiles were obtained for liver, urine and feces as described above. 

The generation of these ribonucleotide adducts are believed to be the result of GI Tract microfloral activity and not enzymatic/metabolic transformations in the cow itself. Such adducts have been well documented as products of antibiotic inactivation produced by various strains of Streptomyces and Staphylococci for a variety of substances such as the lincosaminides (8-11), spectinomycin (12) and streptomycin (13). Furthermore, we have been able to generate pirlimycin 3-(5 -adenylate) by simply incubating pirlimycin with fresh cow manure from untreated cows, although the organisms involved have not been characterized. 

Comparative Metabolism - Rat. Rats were treated orally with a single daily dose of " C-pirlimycin at 29 mg/kg/day for 5 consecutive days. This dose rate was the lowest concentration for which a toxicological response was noted in a 90-day chronic study (Jackson, T. The Upjohn Company, unpublished data. The No Observable Effect Level, NOEL, was 10 mg/kg/day which yields a safe concentration of total residue in muscle, liver, and milk equal to 1.2 ppm, 2.4 ppm, and 0.4 ppm, respectively). Urine and feces were collected at 24-hour intervals throughout the period. The animals were sacrificed at 2 to 3 hours post-last-treatment and liver, kidney, muscle and fat were collected for analysis. Some of the study parameters are summarized in Table VI. 

Table VI, Comparative Metabolism of Pirlimycin in the Rat (Oral) and Cow (IMM) - Dose/Residue Data...

Figure 7. The metabolism scheme for pirlimycin in the dairy cow following intramammary administration of pirlimycin hydrochloride.

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... 

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