Metabolism and disposition of moxonidine in Fischer 344 rats

The metabolism and disposition of moxonidine (4-chloro-5-(imidazolidin-2-yl idenimino)-6-methoxy-2-methylpyrimidine), a potent central-acting antihyper tensive agent, were investigated in F344 rats. After an i.v. or oral admini stration of 0.3 mg/kg of [C-14]moxonidine, the maximum plasma concentration s of moxonidine were determined to be 146.0 and 4.0 ng/ml, respectively, an d the elimination half-lives were 0.9 and 1.1 h, respectively. The oral bio availability of moxonidine was determined to be 5.1%. The metabolic and eli mination profiles of moxonidine were determined after an oral administratio n of 5 mg/kg of [C-14]moxonidine. More than fifteen phase I and phase II me tabolites of moxonidine were identified in the different biological matrice s (urine, plasma, and bile). Oxidative metabolism of moxonidine leads to th e formation of hydroxymethyl moxonidine and a carboxylic acid metabolite as the major metabolites. Several GSH conjugates, cysteinylglycine conjugates , cysteine conjugates, and a glucuronide conjugate were also identified in rat bile samples. The radiocarbon was eliminated primarily by urinary excre tion in rats, with 59.5% of total radioactivity recovered in the urine and 38.4% recovered in the feces within 120 h. In bile duct-cannulated rats, ab out 39.7% of the radiolabeled dose was excreted in the urine, 32.6% excrete d in the bile, and approximately 2% remained in the feces. The results from a quantitative whole body autoradiography study indicate that radiocarbon associated with [C-14]moxonidine and/or its metabolites was widely distribu ted to tissues, with the highest levels of radioactivity observed in the ki dney and liver. In summary, moxonidine is well absorbed, extensively metabo lized, widely distributed into tissues, and rapidly eliminated in rats afte r oral administration.