Oral absorption of anti-AIDS nucleoside analogues. 1. Intestinal transport of didanosine in rat and rabbit preparations.

The intestinal transport of didanosine (ddl), a nucleoside analog used in the treatment of human immunodeficiency virus (HIV) infection, was characterized using in situ and in vitro techniques. The zero-trans uptake of ddl in rat intestinal brush border membrane vesicles (BBMV) was linear over the range of 1 microM to 50 mM, ruling out a significant carrier-mediated absorption component. The lack of carrier-mediated transport was confirmed in a second species (rabbit). In order to quantitate the convective (Pconv) and diffusive (Pdiff) components of ddl intestinal permeability, the steady state wall permeability (P*w) was determined using an established perfusion technique in rats. Even though baseline P*w (pH 6.5, 290 mosm/kg, no modulator) and fluid absorption results were similar to those of furosemide, the ratios (ddl:furosemide) of Pdiff and phi, the sieving coefficient, were 0.31:1 and 1.70:1, respectively, demonstrating that ddl's Pdiff is low and Pconv is high relative to furosemide's, suggesting significant paracellular absorption of ddl. The apparent diffusive absorptive clearances (P'app) of ddl and furosemide were determined in BBMV, which lack functional tight junctions, and the ratios (ddl:furosemide) of P'app in rat and rabbit were 0.23:1 and 0.24:1, respectively. The BBMV results demonstrate that the majority of ddl intestinal transport does not occur by passive membrane diffusion, confirming the single pass intestinal perfusion (SPIP) findings. The results of these studies suggest that ddl is transported by nonfacilitated membrane and paracellular diffusion with paracellular transport being responsible for the majority of ddl absorption from the intestine.