Essentials of insulin pharmacokinetics.

Pharmacokinetic methods are a powerful tool for the investigation of the insulin system in health and disease; the underlying formalisms are simple and straight-foreward. Following intravenous injection the plasma concentration of insulin declines with at least two exponentials, the rapidly disappearing component (half-time 2.4 min) represents elimination from the intravascular space, whereas the most slowly disappearing component (half-time 50-130 min) reflects elimination from the interstitial fluid and the tissues that utilize insulin. Total clearance of insulin, which is the result of metabolic degradation, ranges between 700 and 800 ml/min. The sites of degradation are primarily the liver (hepatic insulin clearance: 320-400 ml/min) and the kidneys (renal insulin clearance: 190-270 ml/min), hence insulin disposal depends on the function of these organs. The apparent volume of distribution for insulin is approximately equal to the extracellular space. Insulin absorption from the subcutaneous tissue is slow (half-times of 0.5-2.7, 6.6-13.8, and 15-48 hours for fast-, intermediate-, and long-acting insulins, respectively). The bioavailability of insulin after subcutaneous administration is variable. Insulin kinetics appear not to be altered in diabetes mellitus, except in cases with insulin antibodies or in insulin-resistant patients, in which insulin removal may be retarded. Optimization of functional insulin replacement requires knowledge of the pharmacokinetic properties of the insulin preparation used.