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 glucosepolymer 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.Perit Dial Int 2015; 35(3):288-296 www.PDIConnect.com epub ahead of print:

Mechanisms of Crystalloid versus Colloid Osmosis across the Peritoneal Membrane

“…34,56 It should be noted that the inclusion of the amylase activity in the TPM could potentially optimize predictions of both net UF and carbohydrate absorption in models using icodextrin. 58 Altogether, these data support the usefulness and reliability of the mouse model of PD to assess icodextrininduced water transport during PD.…”

Substrate Mass Conservation in Enzyme Catalyzed Amylolytic Activity

“…It should be realized that mass conservation concept has been applied in different ways for solving problem of product and by-product distribution or flux using different models, threepole model for instant [19]. Mass conservation study coupled with three-pole model, has application in predicting the peritoneal absorption of icodextrin [19]. = 0, where m is the mass of the reactant [19]).…”

“…Mass conservation study coupled with three-pole model, has application in predicting the peritoneal absorption of icodextrin [19]. = 0, where m is the mass of the reactant [19]).…”

Icodextrin Simplifies Pd Therapy by Equalizing Uf and Sodium Removal among Patient Transport Types during Long Dwells: A Modeling Study

“…The models we used herein are based on the 3-pore model, the current paradigm for modeling peritoneal fluid and solute transport; nonetheless, these models are simplified representations of the physiological processes occurring during PD. Although modeling of ultrafiltration when using icodextrin may still have some limitations, the model we have used herein is the most sophisticated to date (25). To that end, one characteristic feature of our application of the 3-pore model is the lack of difference in fluid transport parameters (i.e.…”

“…Steady-state plasma concentrations of icodextrin metabolites were incorporated to consider patients who routinely use icodextrin (data on file, Baxter Healthcare Corporation). PD Adequest 2.0 was validated for UF and small solute transport (23,24) and this modified kinetic model was previously used to predict icodextrin absorption (25) and sodium removal (6,20).…”