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 molecular weight (M(r)) dextrans were studied in rats. Single intravenous (iv) doses of 1, 25, or 100 mg of fluorescein-labeled dextrans with average M(r) of approximately 4 kD (FD-4) or 150 kD (FD-150) per kilogram of body weight were administered to rats, and serum, urine, and various tissues were collected over time. The samples were analyzed by a sensitive and specific chromatographic method. For FD-150, the area under the serum concentration-time curves (AUCs) increased disproportionately when the dose was increased from 1 to 100 mg/kg; the dose-corrected AUCs were 50.1 +/- 1.9, 85.9 +/- 2.4, and 122 +/- 3 micrograms.h/mL for the doses of 1, 25, and 100 mg/kg, respectively (p < 0.05). This increase in the dose-corrected AUCs was associated with a high and nonlinear accumulation of FD-150 in the liver; that is, the percent dose recovered 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 hand, the serum kinetics of FD-4 exhibited dose independence [the dose-corrected AUCs were 2.38 +/- 0.04, 2.19 +/- 0.07, and 2.30 +/- 0.07 microgram.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 excretion of FD-4 into urine as indicated by the percent doses of FD-4 excreted 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)].(ABSTRACT TRUNCATED AT 250 WORDS)