DISPOSITION OF IDEBENONE (CV-2619), A NEW CEREBRAL METABOLISM IMPROVING AGENT, IN RATS AND DOGS

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After oral administration of ^<14>C-labeled idebenone (^<14>C-CV-2619) to rats, the plasma ^<14>C level reached a plateau at 15 min, which persisted till 8 h and then decreased with a half-life of 4.5 h. In dogs, after oral dosing, the plasma ^<14>C peaked at 15 min, followed by biphasical decline with half-lives of 2.2 and 15.4 h. The plasma of both animals contained mostly metabolites, with a small amount of unchanged CV-2619,which was > 90% protein-bound. In rats given ^<14>C-CV-2619 orally or intravenously, ^<14>C was distributed widely in tissues, with relatively high concns. in the gut, liver and kidney. CV-2619 readily entered the rat brain to undergo subcellular distribution with a significant amount localized in mitochondria. The concn. of ^<14>C in rat fetus was low, as was that in the milk. Oral ^<14>C-CV-2619 was eliminated by rats and dogs mostly as metabolites within 48 h. In rats, more was excreted in urine than in feces, whereas in dogs excretion by these two routes was almost equal. Enterohepatic cycling of biliary ^<14>C occurred in rats. Repeated oral ingestions of ^<14>C-CV-2619 to rats resulted in no accumulation of ^<14>C. The metabolites found in rats and dogs were QS-10,QS-8,QS-6 and QS-4 formed by oxidative shortening of the side chain of CV-2619,and desmethylated CV-2619 and QS-4. Glucuronides and sulfates of the dihydro (quinol) derivatives of the above metabolites were also detected. Dihydro QS-4 sulfate was the major metabolite in plasma and urine of both animals, while dihydro QS-10 glucuronide was predominant in rat bile.
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DISPOSITION OF IDEBENONE (CV-2619), A NEW CEREBRAL METABOLISM IMPROVING AGENT, IN RATS AND DOGS

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