Mapping the time-dependent effects of paricalcitol on serum calcium, phosphorus and parathyroid hormone levels in 5/6 nephrectomized uremic rats

Aims: To investigate whether the frequency of monitoring paricalcitol's impact on serum calcium (Ca), phosphorus and PTH in current clinical practice is sufficient by mapping the time-dependent effects of paricalcitol on these parameters. Main methods: The 5/6 nephrectomized (NX) male, Sprague-Dawley rats with established uremia were treated with vehicle or paricalcitol (0.16 mu g/kg, i.p., 3 X/week). On Day 0 (before treatment), Days 12 and 13 after treatment, and also at 0, 1, 4, 8, 16, 24 h after the last dosing, blood and small intestine samples were collected. Key findings: Serum creatinine and blood urea nitrogen levels were significantly elevated in 5/6 NX rats. Significant increases were observed in serum Ca while PTH decreased by >90% when the parameters were determined at 12 or 13 days after paricalcitol dosing. Paricalcitol caused a step-wise increase in serum Ca levels at 1-24 h following dosing, reduced serum PTH levels with PTH values ranging from 1.06 +/- 0.06 to 26.7 +/- 25.7 pg/ml (vs. 152 +/- 15 pg/ml in Sham rats), but did not affect serum phosphorus in a time-dependent manner. Consistent with the serum Ca data, paricalcitol significantly induced the intestinal expression of Calb3 and TRPV6, genes involved in intestinal Ca transport, and also significantly induced the intestirial calcium absorption. Significance: Our results suggest that the frequency of monitoring paricalcitol's effect on serum Ca, phosphorus and PTH in current clinical practice seems adequate. Additional clinical trials may be needed to resolve the inconsistent clinical observations about the impact of paricalcitol on serum Ca. (C) 2012 Elsevier Inc. All rights reserved.