Studies on the Pharmacokinetics of Ebselen in Rats (2): Absorption, Distribution and Excretion after Repeated Oral Administration.

Abstract

The absorption, distribution and excretion of ebselen were investigated after repeated oral ad ministration of 14C-ebselen to male rats at a daily dose of 50 mg/kg for a maximum of 21 days. 1. The blood levels of radioactivity at 24 hr after dosing reached a steady state by 17th dosing, indicating 4 times higher level than that at the first dosing. After 21st dosing, the blood level of radioactivity reached the Cmax of 8.04 Mg equiv. to ebselen/ml at 2 hr after dosing, eliminated with a half life (t1;2) of 2.37 hr (2-4 hr), reached the second peak at 8 hr and then eliminated with t1/2 of 8.64 day (24-168 hr). The Cmax after 21st dosing was 1.6 times higher, and the elimination rate from 24 hr after dosing was slower, than those parameters in single dosing. 2. After 21st dosing, the level of radioactivity in the limb joint was 7 times higher than that in single dos ing, the levels in the liver, testis and lung were 3 4 times higher, and those in the other tissues were 2 times or less. After final dosing, the levels of radioactivity in thyroid gland and blood cells at 576 hr after dosing were still 41% and 24 °/ of their respective maximum levels, showing relatively slower elimination rates than those observed in the other tissues. 3. The cumulative excretion of radioactivity in urine and feces did not change with the number of dosing after 4th dosing, ranging from 50.2 to 54.7 °o and from 45.4 to 48.3o, respectively, up to 24 hr after every daily dosing. •• OEû • ¶ 'Ì "à ‚Å • ¶ •¬ ‚· ‚é Šˆ•Šˆ•« Ž_ 'f ‚â ƒt ƒŠ•[ ƒ‰ƒWƒJ ƒ‹ ‚ª ŠÖ-^‚· ‚é • ¶ 'Ì •ª Žq,• ¶ 'Ì-OE‚¨‚aeOE‚¨‚ae ‚Ñ'Ÿ Ší ‚Ì Ž_ ‰»‚ª '½-l‚È •a 'Ô ‚É-§ •Ú ‚É ŠÖ˜A ‚à ‚¯ ‚ç ‚ê ‚Ä ‚¢ ‚é ‚± ‚AE‚𠎦 ‚· •ñ •• ‚ª •" '½ ‚-‚È ‚³ ‚ê ‚Ä ‚¢ ‚é1).‚± ‚ê ‚É "º ‚¢,‹ß "N •R Ž_ ‰»•Ü ‚ª '•-Ú‚³ ‚ê,• ‡ •¬ •R Ž_ ‰»•Ü ‚Ì •ì-p‚Ì OE¤‹ † ‚ª •L ‚-•s ‚í ‚ê ‚Ä ‚¢ ‚é.Ebselen, 2-pheny1-1,2-benzisoselenazol-3(2•è)ˆêˆê ˆêˆê •Zne‚Í •ª Žq "à ‚É-L ‹@ ƒZ ƒOEƒ"(Se)‚ð ŠÜ-L‚· ‚é ‰»• ‡ •¨ ‚Å ‚ ‚è,ƒO ƒ‹ ƒ^ ƒ` ƒI ƒ\ ƒy ƒ‹ ƒI ƒL ƒVƒ_ •[ ƒ[(GSH-Px)-l Šˆ•Šˆ•« ‚É Šî ‚à ‚-‰ßŽ_ ‰»Ž‰ Ž¿ ŠÒOE³•ì-p‚¨‚aep‚¨‚ae ‚Ñ ƒŠƒ| ƒL ƒVƒQƒi •[ ƒ[ 'j ŠQ•ì-p‚ð Ž• ‚ •R Ž_ ‰»•Ü ‚Å ‚ ‚é2-4).-{-ò ‚Í "] OEOE ŠÇ •á ŠQ-p"] •Û OEì-ò ‚AE‚µ ‚Ä 'aêê •»-ò Š" Ž®‰ïŽÐ‚É ‚¨‚¢‚¨‚¢ ‚Ä ŠJ "-' † ‚Ì ‰» • ‡ •¨ ‚Å ‚ ‚è,OE» •Ý-{-ò ‚Ì ƒNƒ‚-OE‰º •o OEOE ‚¨‚ae‚¨‚ae ‚Ñ "] •[ •Ç ‹} •« Šú ‚ð 'Î •Û ‚AE‚µ ‚½-Õ •° ŽŽOE±‚ª •i •s ' † ‚Å ‚ ‚é. 'O •ñ5)‚É ‚¨‚¢‚¨‚¢ ‚Ä ‰ä •X ‚Í14C•W Ž¯ ‚µ ‚½ebselen(ˆÈ OEã, 'aêê •»-ò Š" Ž®‰ïŽÐ 'ã ŽÓ•ª •Í OE¤‹ † •Š • §134"OE ‹ž "s •] OEË •ì ‹ae-k Š‹ •¼1-16-13 *'aêê ‰» Šw-ò •i Š" Ž®‰ïŽÐ "OEŠCOE¤‹ † •Š • §319-11ˆï •é OE §"߉ÏOES "OEŠC'º 'º •¼2117