Intestinal absorption and biodistribution of cosalane and its amino acid conjugates: novel anti-HIV agents

Abstract

Cosalane and its amino acid conjugates are potent inhibitors of HIV replication. The purpose of this study was to investigate: (1) the pharmacokinetic disposition of the diglycine (GC) and the diaspartic acid (ASPC) conjugates of cosalane in male Sprague–Dawley rats; (2) intestinal absorption of cosalane and its amino acid conjugates using in vitro (small intestinal segments), in situ (closed loop); and (3) biodistribution of GC and its absolute oral bioavailability in rat. Cosalane and its conjugates exhibited biexponential disposition with very long half-lives upon intravenous dosing. However, these compounds failed to permeate the small intestine unless sodium desoxycholate (5–20 mM) was used as an intestinal permeation enhancer. A rank order correlation in terms of permeation enhancement in a descending order is as follows: GC>Cosalane>ASPC. In situ studies revealed that although the bile salt enhanced the permeation of cosalane across the enterocyte, its hepatic uptake was extensive. However, 66% of the absorbed dose of GC escaped uptake by the reticuloendothelial system (RES) and its biodistribution studies showed that the uptake by the RES was significantly lower compared to the parent compound. GC had an absolute oral bioavailability of 5.10±1.51%. Therefore, GC appears to be a favorable candidate for further development.