Rat model of the hypercalcaemia induced by parathyroid hormone-related protein: characteristics of three bisphosphonates.
In our preliminary experiment, we found that a constant infusion of a high dose of parathyroid hormone-related protein induced both hyperphosphataemia and hypocalcaemia, secondary to renal dysfunction. Therefore, in this study, we developed two types of parathyroid hormone-related protein-induced hypercalcaemia models. One is the hypercalcaemia model, which did not show renal-dysfunction-induced hypocalcaemia. This model might be suitable for estimating hypocalcaemic activities of drugs, especially of those that act on bone resorption. The other is the model for estimating histological changes, which is associated with renal dysfunction. We then used these models to investigate the effects of three different bisphosphonates. Since the hypercalcaemic effect of parathyroid hormone-related protein infusion plateaued at 20 pmol/h, and higher doses of parathyroid hormone-related protein caused an elevation of blood urea nitrogen, the parathyroid hormone-related protein infusion rate was fixed at 20 pmol/h to avoid renal dysfunction and at 40 pmol/h to elicit renal dysfunction. The hypocalcaemic efficiencies of clodronate and etidronate were almost the same but pamidronate was 17.9 times more potent than clodronate. Additionally, both clodronate and pamidronate decreased the plasma concentrations of blood urea nitrogen and the Ca2+ times inorganic P product, whereas etidronate lacked these effects. Clodronate suppressed renal calcification and tubular dilatation in the renal-dysfunction model. These data indicated that clodronate and pamidronate not only decrease the plasma Ca2+ concentration but also improve the renal dysfunction induced by hypercalcaemia.
Komatsu
Yoshimitsu
Y
Central Research Laboratory, R&D, Kissei Pharmaceutical Co. Ltd., 4365-1, Kashiwabara, Hotaka, Minamiazumi, Nagano 399-8304, Japan. yoshimitsu_komatsu@pharm.kissei.co.jp
Imai
Yohsuke
Y
Itoh
Fumiaki
F
Kojima
Masami
M
Isaji
Masayuki
M
Shibata
Nobuo
N
D000818:Animals; D004164:Diphosphonates / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006934:Hypercalcemia / Q000097:blood / Q000139:chemically induced* / Q000188:drug therapy*; D008297:Male; D044162:Parathyroid Hormone-Related Protein / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
D004164:Diphosphonates; D044162:Parathyroid Hormone-Related Protein