Kinetics of Icodextrin

Abstract

Icodextrin isanα-1,4 linked glucose polymer produced by hydrolysis of starch and membrane fractionation to obtain material with the desired molecular weight distribution. Icodextrin is similar in structure to physiological carbohydrates such as glycogen, but the latter has a higher degree of cross-linking through α-1,6 bonds. Icodextrin is a substrate for plasma α-amylase which hydrolyzes it to maltose, maltotriose, and maltotetrose. The fate of icodextrin administered in solution into the peritoneal cavity of patients in renal failure is determined by its stability in the peritoneal fluid, the extent of absorption, probably via the lymphatics, into the systemic circulation, and the rate of hydrolysis by plasma amylase. Early studies on a glucose polymer very similar to icodextrin demonstrated that the compounds are stable in peritoneal fluid from continuous ambulatory peritoneal dialysis (CAPD) patients, but rapidly hydrolyzed by plasma. Absorption of polymer from the peritoneal cavity was approximately 28% during a 12-hour dwell. In these studies it was apparent that hydrolysis products of up to four glucose units readily passed from the blood to the dialysis fluid, but higher molecular weight fragments wereexcluded. In the MIDAS study in which patients were treated with a single daily exchange of 2 L of 7.5% icodextrin, plasma samples were obtained during visit 2 (pretreatment with icodextrin), visit 6 (1 month after commencement of treatment), visit 9 (3 months), and visit 12 (6 months) and analyzed for icodextrin and metabolites. Steady-state plasma levels of icodextrin of approximately 4.6 mg/mL and maltose of 1.1 mg/mL were stable at 1,3, and 6 months. During special studies, when the dwell time for icodextrin and the comparator glucose solutions were controlled to 8 or 12 hours, dialysate was analyzed for polymer and metabolites. Total carbohydrate lost from the dialysate was approximately 19.6% after 8 hours and 33.5% after 12 hours. This compares with a mean of 85.6% of absorbed carbohydrate in 7 patients treated with strong glucose (6 on 3.86%, 1 on 2.27% glucose) for 8 hours. Plasma levels of icodextrin and maltose were measured in 12 patients who stopped once-a-day treatment with the polymer after approximately 2 years. Icodextrin (4.8 mg/mL) and maltose (1.1 mg/mL) fell to pretreatment levels in 7 10 days. On recommencement of treatment with polymer, plasma levels rose to steady-state levels of 4.7 mg/mL for icodextrin and 1.1 mg/mL for maltose in 7 -10 days. Icodextrin in solution in the peritoneal cavity is absorbed into the blood stream, probably via the lymphatic system. The extent of absorption depends on the dwell time of the solution; about 20% of total carbohydrate is absorbed in 8 hours, and this rises to 34% at 12 hours. There is no evidence of metabolism of glucose polymers like icodextrin in the peritoneal cavity. Icodextrin in the systemic circulation is hydrolyzed, probably by plasma and tissue α-amylase, to oligosaccharides, such as maltose, maltotriose and maltotetrose. These may be further metabolized, eliminated by peritoneal dialysis, or, if the patient has residual renal function, excreted in urine. The rapid attainment of steady-state plasma levels of icodextrin and its metabolites and the rapid decline when treatment is stopped is strong evidence against extensive tissue storage of the polymer.