Determination of carrier-mediated transport of 2',3'-dideoxypurine nucleosides in the rat ileum using a bidirectional perfusion technique

Abstract

Purpose: Previous attempts to ascertain the role of uptake and efflux transporters in the oral absorption of anti-HIV dideoxypurine nucleosides have been inconclusive. A novel in situ intestinal perfusion technique with complete mesenteric arterial/venous cannulation was used to examine the asymmetry of ileal dideoxynucleoside permeability under near in vivo conditions.

Methods: Intestinal perfusions were performed in the rat ileum, with cannulation of the artery and vein immediately entering and leaving the segment. Urea and mannitol were used as passive permeability markers, and the directional transport of 2',3'-dideoxyinosine (ddI), 2'-beta-fluoro-2',3'-dideoxyinosine (F-ddI), and 2'-beta-fluoro-2',3'-dideoxyadenosine (F-ddA) were examined.

Results: Urea and mannitol exhibited symmetric permeability (PLtoB = PBtoL), whereas F-ddI and ddI showed significantly higher permeability in blood-to-lumen transport (PBtoL > PLtoB). PBtoL for F-ddA exceeded PLtoB, but the difference did not reach significance at p < 0.05. PBtoL for ddI was demonstrated to be saturable with increasing ddI concentrations, but PLtoB was independent of ddI concentration. PBtoL for ddI was shown to be dependent on sodium concentration and inhibited by probenecid.

Conclusions: Symmetric transport was demonstrated for urea and mannitol as expected for these passive permeability markers. F-ddI and ddI were shown to be preferentially transported from blood to lumen. The basolateral to luminal transport of ddI is saturable, inhibited by probenecid, and sodium ion dependent. These results are consistent with carrier-mediated uptake on the basolateral membrane.