Nephrectomy Decreases Amylin and Pramlintide Clearance in Rats

Abstract

Amylin is a 37 amino acid hormone, co-secreted with insulin from the pancreatic beta-cell in response to nutrient stimuli. Because the human amylin analog, pramlintide, is being tested in patients with diabetes mellitus, a known risk factor for nephropathy, we examined the role of the kidney on amylin and pramlintide metabolism and action in functionally nephrectomized rats. Nephrectomy markedly altered amylin metabolism: it increased incremental area under the plasma amylin concentration curve 3.6-fold (P<0.001) and increased the elimination half-life from 17+/-1 to 26+/-2 minutes (P < 0.01) after subcutaneous injection of 100 microg amylin. Nephrectomy decreased plasma amylin clearance from 20.3+/-1.1 to 7.9+/-0.4 mL/min (P < 0.0001). Thus, at these doses in the rat, the kidney is important for metabolizing amylin and pramlintide.

Glucoregulatory effects and prolonged duration of action of davalintide: a novel amylinomimetic peptide

“…Davalintide, but not amylin, had prolonged effects (up to 8 h) on gastric emptying and glucose levels. Following a single SC injection in rats, the half‐life of davalintide reported here (26 min) is roughly equivalent to that of amylin (17 min) [37], making it unlikely that slower clearance plays a major role davalintide's prolonged actions. While davalintide and amylin showed similar association constants ( K on = 4.4 and 8.8 × 108/M/min, respectively), their dissociation patterns were different.…”

Amylin structure–function relationships and receptor pharmacology: implications for amylin mimetic drug development

“…Amylin metabolism appears to be via a combination of renal clearance and proteolysis to generate a variety of metabolites, such as a des‐Lys metabolite, which is active, and other cleavage products that are unlikely to generate active peptide fragments (Nakazato et al ., ; Watschinger et al ., ; Leckstrom et al ., ; Vine et al ., ). Amylin has a circulating plasma half‐life of approximately 13 min in rats following an intravenous bolus injection (Young, ).…”

Amylin: Pharmacology, Physiology, and Clinical Potential

“…Pramlintide pharmacokinetics is discussed in more detail in section X.A. As with many secreted peptides, amylin (and pramlintide) is metabolized primarily via the kidneys, most likely by proteolytic degradation, and nephrectomized rats exhibit a marked decrease in plasma clearance of amylin (Leckström et al, 1997;Vine et al, 1998a). In vivo, both amylin and pramlintide are rapidly cleaved to their respective des-Lys metabolites.…”

“…However, the strategy of inhibiting degradation of endogenous amylin, as has been successfully used with the dipeptidyl peptidase-IV inhibitors to enhance plasma levels of endogenous active GLP-1 (Holst, 2004), has to date not been evaluated for amylin peptides. Amylin's action is relatively short lived because of its short halflife, and termination of amylin action seems to be mainly due to renal metabolism and excretion (Leckström et al, 1997;Vine et al, 1998a). Therefore, manipulation of its degradation may not be a useful pharmacological approach.…”