Biotransformation of muroctasin in mice.
The main metabolite of N2-[(N-acetylmuramoyl)-L-alanyl-D-isoglutaminyl]-N6-stearoyl-L-lysine MDP-Lys(L18), muroctasin), excreted to the urine and accounting for 15% of the dose, was identified to be R-D-lactic acid by the reverse isotope dilution method in which the metabolite was derivatized to p-bromophenacyl ester, recrystallized and separated into enantiomers by HPLC. The configuration of the lactate moiety in MDP-Lys(L18) was retained during the metabolism. Five metabolites were detected in the liver 5 hours after the administration and 4 of them were identified by TLC as des(GlcNAc)-MDP-Lys(L18), lactic acid, MDP-Lys(L18) and N-acetylmuramic acid in comparison with respective authentic compounds. N-Acetylmuramic acid was confirmed further by the reverse isotope dilution method in which it was converted to peracetylated methyl ester and separated by gas chromatography. It was the main metabolite and accounted for 40% of the radioactivity detected in the liver. MDP-Lys which was supposed to be the pharmacologically active metabolite was not detected. The metabolic pathway in which MDP-Lys(L18) was mainly metabolized to N-acetylmuramic acid, lactic acid and carbon dioxide, successively, was proposed. Some portion of the drug was converted to lactic acid via des(GlcNAc)-MDP-Lys(L18). A novel cleavage reaction of the ether linkage between the 3 position of sugar and lactic acid moiety in N-acetylmuramic acid was observed.
Matsubayashi
K
K
Research Institute, Daiichi Seiyaku Co., Ltd., Tokyo, Japan.
Takegoshi
T
T
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000276:Adjuvants, Immunologic / Q000493:pharmacokinetics*; D000818:Animals; D001711:Biotransformation; D055598:Chemical Phenomena; D002621:Chemistry; D008099:Liver / Q000378:metabolism; D051379:Mice
D000276:Adjuvants, Immunologic; D000119:Acetylmuramyl-Alanyl-Isoglutamine; C036866:romurtide