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_½ 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_β) and volume at steady state (V_ss) 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 < .01 for all parameters except V_β (.014) and V_ss (.012), aggregate vs. monomer]. Thus, in relation to insulin monomer, calculated pharmacokinetic parameters of the aggregate predict accumulation after insulin injection. Plasma t_½ of the aggregate was almost double that of monomeric insulin; total-body clearance and the corresponding volumes of distribution were smaller.