Predicting the Peritoneal Absorption of Icodextrin in Rats and Humans Including the Effect of α-Amylase Activity in Dialysate

Abstract

Background: Contrary to ultrafiltration, the three-pore model predictions of icodextrin absorption from the peritoneal cavity have not yet been reported likely, in part, due to difficulties in estimating the degradation of glucose-polymer chains by α-amylase activity in dialysate. We incorporated this degradation process in a modified three-pore model of peritoneal transport to predict ultrafiltration and icodextrin absorption simultaneously in rats and humans.

Methods: Separate three-pore models were constructed for humans and rats. The model for humans was adapted from PD Adequest 2.0 including a clearance term out of the peritoneal cavity to account for the absorption of large molecules to the peritoneal tissues, and considering patients who routinely used icodextrin by establishing steady-state plasma concentrations. The model for rats employed a standard three-pore model in which human kinetic parameters were scaled for a rat based on differences in body weight. Both models described the icodextrin molecular weight (MW) distribution as five distinct MW fractions. First order kinetics was applied using degradation rate constants obtained from previous in-vitro measurements using gel permeation chromatography. Ultrafiltration and absorption were predicted during a 4-hour exchange in rats, and 9 and 14-hour exchanges in humans with slow to fast transport characteristics with and without the effect of amylase activity.

Results: In rats, the icodextrin MW profile shifted towards the low MW fractions due to complete disappearance of the MW fractions greater than 27.5 kDa. Including the effect of amylase activity (60 U/L) resulted in 21.1% increase in ultrafiltration (UF) (7.6 mL vs 6.0 mL) and 7.1% increase in icodextrin absorption (CHO) (62.5% with vs 58.1%). In humans, the shift in MW profile was less pronounced. The fast transport (H) patient absorbed more icodextrin than the slow transport (L) patient during both 14-hour (H: 47.9% vs L: 40.2%) and 9-hour (H: 37.4% vs L: 31.7%) exchanges. While the UF was higher during the longer exchange, it varied modestly among the patient types (14-hour range: 460 - 509 mL vs 9-hour range: 382 - 389 mL). When averaged over all patients, the increases in UF and CHO during the 14-hour exchange due to amylase activity (7 U/L) were 15% and 1.5%, respectively.

Conclusion: The icodextrin absorption values predicted by the model agreed with those measured in rats and humans to accurately show the increased absorption in rats. Also, the model confirmed the previous suggestions by predicting an increase in UF specific to amylase activity in dialysate, likely due to the added osmolality by the small molecules generated as a result of the degradation process. As expected, this increase was more pronounced in rats than in humans because of higher dialysate concentrations of amylase in rats.

Keywords: Icodextrin; absorption; amylase activity; ultrafiltration.

Figure 1 —

Change in icodextrin mass at 20 U/L amylase concentration as a function of icodextrin MW at 10 hours: (a) in-vitro measurement of refractive index (RI) using chromatography (adapted from Nishimura et al. (13) with permission), (b) the mass degradation profile as a function of icodextrin MW implemented in the present model.

Figure 2 —

Predicted time-dependent concentration profiles of the five icodextrin MW fractions. Increasing MW fractions: fraction 1 (solid line), fraction 2 (dashed line); decreasing MW fractions: fraction 3 (solid line); fraction 4 (dotted-dashed line); fraction 5 (dashed line).

Figure 3 —

Icodextrin MW fraction concentrations at the start and at the end of a 4-hour dwell in a rat. Predicted concentrations (top); measured concentrations (adapted from Garcia-Lopez and Lindholm (12) with permission) (bottom). Icodextrin concentrations at the start of the dwell (or the measured control solution concentration) (open squares), at the end of 4 hours (closed circles), at the end of 4 hours without any icodextrin degradation, C_A= 0 (dashed lines). MW = molecular weight; Da = daltons; T = time; C_A = average dialysate amylase concentration.

Figure 4 —

Predicted ultrafiltration profile in a rat during a 4-hour dwell with amylase activity, C_A=60 U/L (solid line) and without amylase activity, C_A= 0 (dashed line). C_A = average dialysate amylase concentration.

Figure 5 —

Predicted icodextrin MW fraction concentrations at the start and at the end of 9-hour (top) and 14-hour (bottom) exchanges in a high-average transport patient. Icodextrin concentrations at the start of the dwell, open squares; at the end of the dwell with degradation (closed circles) and without degradation, C_A= 0 (dashed lines). MW = molecular weight; Da = daltons; T = time; C_A = average dialysate amylase concentration.

Figure 6 —

Predicted ultrafiltration profile in humans averaged over the four patient transport types, with amylase activity, CA=7 U/L (solid line) and without amylase activity, C_A= 0 (dashed line). C_A = average dialysate amylase concentration.