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

Abstract

The intestinal transport of didanosine (ddl), a nucleoside analog used in the treatment of human immunodeficiency virus (HIV) infection, was characterized usingin situandin vitrotechniques. The zero-trans uptake of ddl in rat intestinal brush border membrane vesicles (BBMV) was linear over the range of 1 μM 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 (Pw) was determined using an established perfusion technique in rats. Even though baselinePw(pH 6.5, 290 mosm/kg, no modulator) and fluid absorption results were similar to those of furosemide, the ratios (ddl:furosemide) ofPdiffand ø, the sieving coefficient, were 0.31:1 and 1.70:1, respectively, demonstrating that ddl'sPdiffis low andPconvis high relative to furosemide's, suggesting significant paracellular absorption of ddl. The apparent diffusive absorptive clearances (Papp) of ddl and furosemide were determined in BBMV, which lack functional tight junctions, and the ratios (ddl:furosemide) ofPappin 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.