title: Renal tolerability profile of novel, potent bisphosphonates in two short-term rat models.
abstract: Bisphosphonates are used clinically to inhibit bone resorption but they may also cause renal damage. For the profiling of new potent bisphosphonates, their adverse renal effects were investigated in 2 rat models. In the first model, bisphosphonate was repeatedly injected (1 mg/kg, subcutaneously) over 2 weeks and the urinary excretion of malate dehydrogenase was monitored to assess nephrotoxic potential. Of the 6 new compounds tested, 3 markedly elevated malate dehydrogenase whereas 3 others caused only minor changes similar to those observed with 6 reference bisphosphonates that are already used clinically. On the basis of a therapeutic index (inhibition of bone resorption versus renal effects) 7-180 fold greater than that of other analogues, the compound CGP 42446 was further profiled. In the second model, CGP 42446 or pamidronate was infused (1.5-50 mg/kg, intravenously) into anaesthetized rats and the serum urea concentration was monitored as an indicator of renal dysfunction. Both compounds elevated serum urea in a time- and dose-dependent manner, but the ED100 value for CGP 42446 was 3.8-fold higher than that of pamidronate. It is concluded that CGP 42446 (zoledronate) has a low nephrotoxic potential and can be further developed as a new potent inhibitor of bone resorption.
authors.affiliation: Ciba-Geigy Ltd., Pharmaceuticals Division, Basel, Switzerland.
authors.forename: J R
authors.initials: JR
authors.lastname: Green
authors.forename: Y
authors.initials: Y
authors.lastname: Seltenmeyer
authors.forename: K A
authors.initials: KA
authors.lastname: Jaeggi
authors.forename: L
authors.initials: L
authors.lastname: Widler
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000188:drug therapy; D004164:Diphosphonates / Q000494:pharmacology / Q000633:toxicity*; D004195:Disease Models, Animal; D007279:Injections, Subcutaneous; D007668:Kidney / Q000187:drug effects / Q000502:physiology; D007674:Kidney Diseases / Q000139:chemically induced*; D008297:Male; D010280:Parathyroid Glands / Q000502:physiology / Q000601:surgery; D051381:Rats; D011919:Rats, Inbred Strains; D013961:Thyroid Gland / Q000502:physiology / Q000601:surgery; D013965:Thyroidectomy
chemical_list: D004164:Diphosphonates