Cinacalcet HCl, an allosteric modulator of the
calcium-sensing receptor (CaR), has recently been approved for the treatment of
secondary hyperparathyroidism in patients with
chronic kidney disease on dialysis, due to its suppressive effect on
parathyroid hormone (PTH) secretion. Although
cinacalcet's effects in patients with primary and
secondary hyperparathyroidism have been reported, the crucial relationship between the effect of calcimimetics and CaR expression on the parathyroid glands requires better understanding. To investigate its suppressive effect on PTH secretion in
primary hyperparathyroidism, in which
hypercalcemia may already have stimulated considerable CaR activity, we investigated the effect of
cinacalcet HCl on PTH-
cyclin D1 transgenic mice (PC2 mice), a model of
primary hyperparathyroidism with hypo-expression of CaR on their parathyroid glands. A single administration of 30 mg/kg
body weight (BW) of
cinacalcet HCl significantly suppressed serum
calcium (Ca) levels 2 h after administration in 65- to 85-week-old PC2 mice with chronic biochemical
hyperparathyroidism. The percentage reduction in serum PTH was significantly correlated with CaR hypo-expression in the parathyroid glands. In older PC2 mice (93-99 weeks old) with advanced
hyperparathyroidism, serum Ca and PTH levels were not suppressed by 30 mg
cinacalcet HCl/kg. However, serum Ca and PTH levels were significantly suppressed by 100 mg/kg of
cinacalcet HCl, suggesting that higher doses of this compound could overcome severe
hyperparathyroidism. To conclude,
cinacalcet HCl demonstrated potency in a murine model of
primary hyperparathyroidism in spite of any presumed endogenous CaR activation by
hypercalcemia and hypo-expression of CaR in the parathyroid glands.