Disposition of idebenone (CV-2619), a new cerebral metabolism improving agent, in rats and dogs.

Abstract

After oral administration of 14C-labeled idebenone (14C-CV-2619) to rats, the plasma 14C 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 14C peaked at 15 min, followed by biophysical 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 greater than 90% protein-bound. In rats given 14C-CV-2619 orally or intravenously, 14C 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 14C in rat fetus was low, as was that in the milk. Oral 14C-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 14C occurred in rats. Repeated oral ingestions of 14C-CV-2619 to rats resulted in no accumulation of 14C. 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.

Potential Antifibrotic and Angiostatic Impact of Idebenone, Carnosine and Vitamin E in Nano-Sized Titanium Dioxide-Induced Liver Injury

“…On the other hand, the reduction in hepatic enzyme levels following the administration of these antioxidants implied their possible protective effect on hepatocytes. In agreement, idebenone was reported to protect against bile acid-induced hepatocellular injury and lipid peroxidation [10]. Carnosine protected the liver against ischemia and lowered the markers of liver damage (ALT, AST and myeloperoxidase) [29].…”

“…Treatment with idebenone, carnosine, vitamin E and their combination alleviated these changes to a variable degree. Previously, idebenone has been shown to protect against hepatocellular injury and prevent hydroperoxide production [10]. Carnosine significantly alleviated oxidative stress by increasing reduced glutathione (GSH) content, decreasing the formation of malondialdehyde (MDA), ROS, and oxidized glutathione (GSSG), and retaining the activity of glutathione peroxidase (GPx) and superoxide dismutase (SOD) in liver [33].…”

“…Idebenone [2, 3-dimethoxy-5-methyl-6-(10-hydroxydecyl)-1,4 benzoquinone] is a synthetic analog of coenzyme Q10 (CoQ10), the vital cell membrane antioxidant and essential constituent of the ATP-producing mitochondrial electron transport chain (ETC) [8]. Idebenone is a potent antioxidant; it has the ability to operate under low oxygen tension situations and to cause inhibition of lipid peroxidation [9,10]. Carnosine (b-alanyl-L-histidine) is highly concentrated in muscle and brain tissues.…”

Oral Administration of NGF Synthesis Stimulators Recovers Reduced Brain NGF Content in Aged Rats and Cognitive Dysfunction in Basal – Forebrain – Lesioned Rats

“…These differences may be due to differences in the distribution of idebenone and propentofylline in discrete brain areas after oral administration. It is dif ficult to confirm whether this is so, however, since no autoradiographic method for the de tection of idebenone has yet been established and since propentofylline at the doses used, and when administered orally, cannot be de tected in the brain, even by autoradiographic methods [17,18].…”

“…It has been reported that idebenone [6-(10-hydroxydecyl) -2,3-dimethoxy-5-methyl-1,4-benzoquinone], a benzoquinone deriva tive, and propentofylline [3,7-dihydro-3-methyl -1 -(5-oxohexyl)-7-propyl-1 H-purine -2,6 dione], a xanthine derivative, stimulate NGF synthesis and secretion in quiescent as troglial cells [15,16], Since these molecules can cross the blood-brain barrier [17,18], they could be expected to stimulate NGF synthesis in the brain; indeed we found that both drugs recovered the reduced NGF con tent in the brains of aged rats. Further, both drugs ameliorated cognitive dysfunction in basal-forebrain-lesioned rats.…”