DOSE-DEPENDENCY OF THE KINETICS OF DEXTRANS IN RATS - EFFECTS OF MOLECULAR-WEIGHT

The effects of dose on the serum and tissue kinetics of high and low m olecular weight (M(r)) dextrans were studied in rats. Single intraveno us (iv) doses of 1, 25, or 100 mg of fluorescein-labeled dextrans with average M(r) of similar to 4 kD (FD-4) or 150 kD (FD-150) per kilogra m of body weight were administered to rats, and serum, urine, and vari ous tissues were collected over time. The samples were analyzed by a s ensitive and specific chromatographic method. For FD-150, the area und er the serum concentration-time curves (AUCs) increased disproportiona tely when the dose was increased from 1 to 100 mg/kg; the dose-correct ed AUCs were 50.1 +/- 1.9, 85.9 +/- 2.4, and 122 +/- 3 mu g . h/mL for the doses of 1, 25, and 100 mg/kg, respectively (p < 0.05). This incr ease in the dose-corrected AUCs was associated with a high and nonline ar accumulation of FD-150 in the liver; that is, the percent dose reco vered in the liver decreased from 68.5 +/- 2.4% to 41.5 +/- 3.4% when the dose was increased from 1 to 100 mg/kg (p < 0.05). On the other ha nd, the serum kinetics of FD-4 exhibited dose independence [the dose-c orrected AUCs were 2.38 +/- 0.04, 2.19 +/- 0.07, and 2.30 +/- 0.07 mu g . h/mL for the doses of 1, 25, and 100 mg/kg, respectively (p > 0.05 )]. This dose independence was attributed to a high and linear excreti on of FD-4 into urine as indicated by the percent doses of FD-4 excret ed into urine [i.e., 82.0 +/- 1.8, 78.7 +/- 4.4, and 82.2 +/- 7.2 for the doses-of 1, 25, and 100 mg/kg, respectively (p > 0.05)]. The resul ts of these studies indicate that the dose dependency of the kinetics of dextrans is influenced by their elimination pathway, which is diffe rent for the low and high M(r) dextrans.