ENHANCEMENT OF INTESTINAL INSULIN ABSORPTION BY BILE-SALT FATTY-ACID MIXED MICELLES IN DOGS

The pharmacokinetics and pharmacodynamics of porcine zinc insulin foll owing intravenous (iv), intrajejunal, and ileocolonic delivery were ev aluated in dogs. The concentration-time profile of plasma immunoreacti ve insulin following iv injection could be best described by a two-com partment model with a mean distribution half-life of 1.1 min and a mea n elimination half-life of 5.6 min. Maximum hypoglycemia occurred at 1 5 min after injection. Intrajejunal administration of 10 units/kg insu lin in phosphate-buffered saline resulted in minimal insulin absorptio n or hypoglycemia. Incorporation of mixed micelles containing 30 mM so dium glycocholate and 40 mM linoleic acid significantly improved enter al insulin absorption. When delivered with mixed micelles, the mean ab solute bioavailability of insulin was 1.8%. To study the effect of int estinal site on insulin uptake, the same formulation was delivered to the ileocolonic region. The mean absolute bioavailability of insulin a bsorbed from this site was 0.6%. Delivery of insulin to both sites cau sed significant hypoglycemia in all dogs. Insulin combined with mixed micelles is enterally absorbed in dogs; however, the bioavailability i s much lower than that observed in similar studies with rats.