MOLECULAR-WEIGHT DEPENDENT TISSUE ACCUMULATION OF DEXTRANS - IN-VIVO STUDIES IN RATS

The effects of molecular weight (M,) on the serum and urine pharmacoki netics and tissue distribution of dextrans, potential macromolecular c arriers for drug delivery, were studied in rats. A single 5 mg/kg dose of fluorescein-labeled dextrans (FDs) with a M(r) of 4000 (FD-4), 20 000 (FD-20), 70 000 (FD-70), or 150 000 (FD-150) was administered into the tail vein of separate groups of rats. At different times after th e administration of each FD, animals were sacrificed, and blood, urine , and various tissues were obtained. The concentrations of FDs in the samples were subsequently determined by using a sensitive and specific high performance size exclusions chromatographic method. Among the ti ssues studied, high accumulation of dextrans was found only in the liv er (liver:serum AUC ratios less than or equal to 29) and spleen (splee n:serum AUC ratios less than or equal to 10), with high concentrations in these tissues persisting even at the last sampling time (96 h). In contrast, the serum concentrations of the studied FDs were not measur able beyond 12 h. The serum and urine kinetics and the liver, spleen, and kidney accumulation of FDs demonstrated a significant degree of M( r) dependency. The total and renal clearance of FDs consistently decre ased with an increase in M,. However, the effects of M,on the tissue a ccumulation of dextrans was tissue dependent. For the liver, the tissu e:serum AUC ratios increased from 0.346 for FD-4 to 15.2 for FD-20 and 28.8 for FD-70, while a further increase in M(r) to 150 kDa (FD-150) resulted in lowering the ratio to 8.59 in this tissue. For the spleen, the ratios increased from 0.095 for FD-4 to 9.56 for FD-150. For the kidneys, an opposite M(r) dependency was observed, as the ratios decre ased from 3.49 for FD-4 to 0.003 for FD150. The data presented here ma y be used for optimal design of dextran-drug conjugates for delivery t o specific tissues such as the liver.