Pharmacokinetic model of circulating covalent aggregates of insulin.
Covalent aggregates of insulin in blood of insulin-treated diabetic patients account for as much as 70% (mean 28 +/- 3.6%) of serum insulin immunoreactivity. These aggregates may originate in therapeutic insulin, because similar substances account for 0.1-3% of these preparations. Larger amounts in blood imply that aggregates accumulate as a result of delayed clearance. To test and quantify this speculation, we calculated the plasma kinetics of this material in four normal volunteers who received large intravenous doses (30 mU.kg-1.min-1) of beef-pork crystalline zinc insulin for 120 min. Insulin aggregate and monomer concentrations were measured in blood samples obtained at regular intervals throughout the infusion and during 4 h after discontinuation of insulin. Pharmacokinetic parameters were calculated from the data. Insulin aggregate and monomer serum t 1/2 were 63.6 +/- 6.9 and 34.3 +/- 2.8 min, respectively, and clearances were 101 +/- 10 and 232 +/- 47 ml/min. Volume of distribution (V beta) and volume at steady state (Vss) were 9.1 +/- 1.8 and 8.2 +/- 2.2 L for insulin aggregate and 11.6 +/- 2.8 and 12.2 +/- 3.6 L for insulin monomer, respectively. Mean residency time was 141 +/- 14 and 114 +/- 10 min for insulin aggregate and monomer, respectively [P less than .01 for all parameters except V beta (.014) and Vss (.012), aggregate vs. monomer]. Thus, in relation to insulin monomer, calculated pharmacokinetic parameters of the aggregate predict accumulation after insulin injection. Plasma t 1/2 of the aggregate was almost double that of monomeric insulin; total-body clearance and the corresponding volumes of distribution were smaller.
Maislos
M
M
Department of Medicine, Ben-Gurion University, Beer Sheva, Israel.
Bialer
M
M
Mead
P M
PM
Robbins
D C
DC
D000328:Adult; D003922:Diabetes Mellitus, Type 1 / Q000097:blood; D004340:Drug Contamination; D006801:Humans; D007262:Infusions, Intravenous; D007328:Insulin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male
D007328:Insulin