       Document 0334
 DOCN  M9630334
 TI    Oral absorption of anti-AIDS nucleoside analogues. 1. Intestinal
       transport of didanosine in rat and rabbit preparations.
 DT    9603
 AU    Sinko PJ; Hu P; Waclawski AP; Patel NR; Department of Pharmaceutics,
       College of Pharmacy, Rutgers; University, Piscataway, NJ 08855, USA.
 SO    J Pharm Sci. 1995 Aug;84(8):959-65. Unique Identifier : AIDSLINE
       MED/96010379
 AB    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.
 DE    Animal  Antiviral Agents/*PHARMACOKINETICS  Biological Availability
       Didanosine/*PHARMACOKINETICS  Diffusion  Diuretics,
       Sulfamyl/PHARMACOLOGY  Female  Furosemide/PHARMACOLOGY  Human  HIV/*DRUG
       EFFECTS  In Vitro  Intestinal Absorption  Male  Microvilli/METABOLISM
       Permeability  Rabbits  Rats  Rats, Sprague-Dawley  Support, Non-U.S.
       Gov't  Support, U.S. Gov't, P.H.S.  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

