Studies on the Pharmacokinetics of Ebselen in Rats (1): Absorption, Distribution, Metabolism and Excretion after Single Oral Administration.

Abstract

The absorption, distribution, metabolism and excretion of ebselen were investigated by single oral administration of radio-labelled 14C-ebselen to fasted male rats at a dose of 50 mg/kg. 1. The radioactivity in plasma reached the Cmax of 14.78,ug equiv. to ebselen/ml at 1 hr after administra tion, eliminated with an apparent half-life (t1/2) of 2.1 hr (1-3 hr), reached the second peak at 4 hr, eliminat ed with t1/2 of 6.6 hr (4-8 hr), reached the third peak at 12 hr, and then eliminated. 2. The radioactivity was distributed to tissues, reaching maximum levels by 2 hr after administration in most part of tissues. Relatively higher levels of radioactivity were observed in fat, brown fat, adrenal gland, skin, liver, Harderian gland and kidney. The levels of radioactivity in most part of tissues were comparable with or higher than that in plasma. At 96 hr after administration, the levels of radioactivity in all the tissues were reduced to 0.1% or less of their maximum levels, showing little retention of radioactivity in tissues. The binding ratio of radioactivity to blood cells was 4.5-28.4% from 0.5 to 12 hr after administration, and then increased with time and almost all radioactivity in blood was found in blood cells at 72 hr after adminis tration. The binding ratio of radioactivity to plasma proteins was high, being 92-97% from 1 to 24 hr after ad ministration. After charcoal treatment, 14% of the initial radioactivity remained in the plasma sample at 1 hr after administration. The binding ratio of radioactivity to plasma proteins was 99% or more when 0.2-20 yg/ml of 14C-ebselen was added to blank plasma samples. After charcoal treatment, 71% of the initial radioactivity remained in the plasma sample after addition of 18 jug/Ml of 14C-ebselen. 3. Unchanged ebselen is not found in urine, plasma or bile. A selenosulfide (Se-S) complex formed from ebselen with plasma thiol proteins, S-[2-(phenylcarbamoyl)phenylseleno] protein (Se-S complex, "protein" represents mainly albumin in plasma) was found in plasma. The Se-S complex concentration was determined as the radioactivity which was released from plasma proteins by dithiothreitol reduction after sin gle oral administration of 14C-ebselen to male rats. The Se-S complex concentration in plasma reached the Cm,, of 3.39,ug eq. to ebselen/ml at 1 hr after administration and eliminated with an apparent half-life of 7 hr. The complex could be reduced, forming a selenol intermediate. The Se atom in the selenol is proposed to be methylated or glucuronidated, forming M-7 and M-1, respectively, and M-7 is proposed to be further oxi dized, forming M-4. M-7, M-4 and polar metabolites including M-1 were found in plasma after single oral administration of 14C-ebselen to male rats. 4. The radioactivity was excreted almost completely within 48 hr after administration. Within 96 hr after administration, 58.9% of radioactivity was excreted in urine and 40.1% of that in feces.