The metabolic fates of milbemycin A3 and A4 (M. A3 and M. A4) were examined by oral administration of M. A3 and M. A4 labeled with 3H at 5-position to male and female rats at 5 mg/kg. The administered 3H was almost completely excreted in the urine and feces within 7 days after administration of 3H-M. A3 or 3H-M. A4. 3H levels remained relatively high in the fat and liver, while 3H in the tissues rapidly decreased to a very low level 7 days after administration.Concentrations of 3H and the parent compound in the tissues were lower in rats treated with 3H-M. A3 than in those treated with 3H-M. A4, suggesting M. A3 was metabolized faster than M. A4. 13-Hydroxylated M. A3/A4 (13-OH-A3/A4) was a major metabolite in the tissues and dihydroxylated M. A3/A4 ((OH)2-A3/A4) in the urine. In the feces, M. A3/A4, 13-OH-A3/A4, (OH)2-A3/A4 and polar metabolites were found.M. A3/A4 were predominantly metabolized to 13-OH-A3/A4 and subsequently to (OH)2-A3/A4, which were supposed to be further metabolized to polar metabolites.No essential difference was observed in the metabolic fates between M. A3 and M. A4 in the rats. The in situ intestinal absorption of M. A3 was faster than that of M. A4.
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