RT Journal Article
SR Electronic
T1 Pharmacokinetics, Biliary Excretion, and Tissue Distribution of Novel Anti-HIV Agents, Cosalane and Dihydrocosalane, in Sprague-Dawley Rats
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 403
OP 408
VO 28
IS 4
A1 Kameswara R. Kuchimanchi
A1 Chandrasekhar Udata
A1 Thomas P. Johnston
A1 Ashim K. Mitra
YR 2000
UL http://dmd.aspetjournals.org/content/28/4/403.abstract
AB Cosalane and dihydrocosalane are potent inhibitors of HIV replication with a broad range of activity. The purpose of this study was to investigate: 1) the pharmacokinetic disposition of both cosalane and dihydrocosalane in male Sprague-Dawley rats, and 2) biliary excretion, enterohepatic circulation, and tissue distribution of cosalane after i.v. and/or oral administration. Animals were administered i.v. (10 mg/kg) cosalane or dihydrocosalane through a jugular vein to obtain plasma profiles. Dose dependence of cosalane was studied over a dose range of 1.0 to 10 mg/kg. The extent of enterohepatic recycling, biliary excretion, and tissue distribution were studied after i.v. administration. Both cosalane and dihydrocosalane exhibited a biexponential disposition with very long half-lives of 749 ± 216 and 1016 ± 407 min, along with very large volumes of distribution 23.1 ± 4.4 and 24.4 ± 2.5 liter/kg, respectively. Both cosalane (nondetectable) and dihydrocosalane (<1%) showed very poor oral bioavailability. The biliary and renal excretions of cosalane were found to be negligible with no detectable metabolites either in urine or bile. After oral administration, more than 87% of the cosalane dose was excreted in the feces as the parent compound. Also, cosalane was sequestered significantly in liver with quantifiable levels in all tissues tested, even 48 h after the dose was administered. Therefore it was concluded that the poor oral bioavailability of cosalane may be due to its poor enterocytic transport coupled with sequestration in liver parenchymal cell membrane layers. The American Society for Pharmacology and Experimental Therapeutics