Pharmacokinetics, biliary excretion, and tissue distribution of novel anti-HIV agents, cosalane and dihydrocosalane, in Sprague-Dawley rats

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 ma le 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 thr ough 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 enterohepat ic recycling, biliary excretion, and tissue distribution were studied after i.v. administration. Both cosalane and dihydrocosalane exhibited a biexpon ential disposition with very long half-lives of 749 +/- 216 and 1016 +/- 40 7 min, along with very large volumes of distribution 23.1 +/- 4.4 and 24.4 +/- 2.5 liter/kg, respectively. Both cosalane (nondetectable) and dihydroco salane (<1%) showed very poor oral bioavailability. The biliary and renal e xcretions of cosalane were found to be negligible with no detectable metabo lites 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, c osalane 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 parench ymal cell membrane layers.