Abstract

The pharmacokinetics of fluorescein-labeled dextran with a MW of 70,000 (FD-70) were studied after i.v. injection of single 5-mg/kg doses to control (C), untreated diabetic (D) and insulin-treated diabetic rats. Concentrations of FD-70 in serum, urine and various tissues were determined using a size exclusion chromatographic method. Untreated diabetes caused a striking change in the elimination parameters of FD-70, whereas the distribution parameters were mostly unaffected by the disease. The area under the serum concentration-time curve (microgram-hr/ml) in D rats (1360 +/- 506) was approximately 8 times that in C rats (175 +/- 16). Consistent with this, the terminal harmonic half-lives of FD-70 in D and C rats were 16.1 and 1.80 hr, respectively. Although the renal clearance of the macromolecule was similar in the two groups, the differences in the area under the serum concentration-time curve values could be accounted for by the substantially lower nonrenal clearance of FD-70 in D rats (0.0297 +/- 0.0296 vs. 0.434 +/- 0.050 ml/min/kg). At 12 hr after the administration of FD-70, concentrations of the macromolecule in the heart, lung, brain and kidneys were negligible. However, the C and D livers contained 53.3 +/- 11.2 and 14.0 +/- 6.8% of the administered dose at this time. Most of the diabetes effects on the disposition of FD-70 were reversed by chronic insulin treatment. It is concluded that the significant differences between D and C rats in their serum concentration-time profiles of FD-70 are likely due to differences in their liver accumulation of the macromolecule.