Mechanisms of Amylin Elimination

The kinetics of elimination for insulin and amylin differed, with amylin having a longer half-life. This conclusion was supported by a mathematical model of b-cell peptide kinetics, in which clearance of amylin secreted in response to a glucose challenge was 2.6- to 4-fold lower than that of insulin (0.034-0.053 versus 0.14 min-1, respectively) (Thomaseth et al., 1996). The comparatively rapid elimination of insulin was due in large part to extraction on its first pass through the liver. In an isolated perfused liver preparation, ^50% of insulin was extracted on the first pass, while extraction of amylin was minimal (Nishimura et al., 1992).

In contrast, nephrectomy markedly reduced amylin and pramlintide clearance in rats (Smith et al., 1996; Vine et al., 1996, 1998), indicating a major role for the kidney in clearance. This interpretation concurred with observations that metabolism by the kidney is also a critical route of elimination for many peptide hormones (Ardaillou and Paillard, 1980; Ardaillou et al., 1970; Jorde et al., 1981; Rabkin and Kitaji, 1983). For example, renal metabolism appeared responsible for elimination of up to 60% of the mammalian calcitonins (Ardaillou et al., 1970), which structurally and functionally resemble amylin. The changes in amylin metabolism produced by nephrectomy were similar to those observed for calcitonin (Foster et al., 1972) (Fig. 4).

Renal clearance of amylin inferred from nephrectomy studies was greater than glomerular filtration rate, and instead approached the value for renal plasma flow (Vine et al., 1998) (Fig. 5), the implication being that plasma was cleared of amylin immunoreactivity not merely by filtration, but by renal peptidases associated with the vascular supply.

Amylin concentrations are elevated in renal failure (for example, 15.1 ± 3.2 versus 3.2 ± 0.2 pM; Ludvik et al., 1994) (Clodi et al., 1996; Ludvik et al., 1990; Watschinger et al., 1992), as is the case for other hormones metabolized by the kidney.

Enhanced responses in isolated skeletal muscle after application of protease inhibitors led to the proposal that muscle interstitium may also have been a site of degradation (Leighton et al., 1992).

Amylin appeared not to cross the placental barrier at any appreciable rate. After administration of pramlintide to pregnant rats, concentrations in the amniotic fluid and fetal plasma were ~20 pM (1/5000 that of the maternal circulation) and were not different from levels of endogenous rat

FIGURE 5 Changes in plasma concentrations of rat amylin (left panel) and pramlintide (right panel) in anesthetized rats with and without acute functional nephrectomy. Data from Vine et al. (1998).

Time (h) of infusion at 1 jig/h Time (h) of infusion at 1 ¿¿g/h

FIGURE 5 Changes in plasma concentrations of rat amylin (left panel) and pramlintide (right panel) in anesthetized rats with and without acute functional nephrectomy. Data from Vine et al. (1998).

amylin detected with the same assay prior to administration (Gedulin, unreported data). In the same preparation, human amylin, which was distinguishable from endogenous rat amylin, was undetectable in most fetal samples, despite being present at 8.8 nM (>10,000 times the limit of detection) in the maternal circulation.

In a 2-hr ex vivo perfusion of isolated human placental cotyledons, the ratio of maternal to fetal pramlintide concentration was ^500, indicating a low propensity of that amylin analog to cross the placenta (Hiles et al., 2002, 2003).

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