title: Biodistribution and plasma protein binding of zoledronic acid.
abstract: The bisphosphonate zoledronic acid is a potent inhibitor of osteoclast-mediated bone resorption. To investigate drug biodistribution and elimination, (14)C-zoledronic acid was administered intravenously to rats and dogs in single or multiple doses and assessed for its in vitro blood distribution and plasma protein binding in rat, dog, and human. Drug exposure in plasma, bones, and noncalcified tissues was investigated up to 240 days in rats and 96 h in dogs using radiometry after dissection. Drug biodistribution in the rat and within selected bones from dog was assessed by autoradiography. Concentrations of radioactivity showed a rapid decline in plasma and noncalcified tissue but only a slow decline in bone, to approximately 50% of peak at 240 days post dose, whereas the terminal half-lives (50-200 days) were similar in bone and noncalcified tissues, suggesting redistribution of drug from the former rather than prolonged retention in the latter. Uptake was highest in cancellous bone and axial skeleton. At 96 h after dose, the fraction of dose excreted was 36% in rat and 60% in dog; 94 to 96% of the excreted radioactivity was found in urine. Blood/plasma concentration ratios were 0.52 to 0.59, and plasma protein binding of zoledronic acid was moderate to low in all species. The results suggest that a fraction of zoledronic acid is reversibly taken up by the skeleton, the elimination of drug is mainly by renal excretion, and the disposition in blood and noncalcified tissue is governed by extensive uptake into and slow release from bone.
authors.affiliation: Novartis Pharma AG, DMPK, WSJ-210.4.25, CH-4002 Basel, Switzerland. markus.weiss@novartis.com
authors.forename: H Markus
authors.initials: HM
authors.lastname: Weiss
authors.forename: Ulrike
authors.initials: U
authors.lastname: Pfaar
authors.forename: Alain
authors.initials: A
authors.lastname: Schweitzer
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Wiegand
authors.forename: Andrej
authors.initials: A
authors.lastname: Skerjanec
authors.forename: Horst
authors.initials: H
authors.lastname: Schran
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001345:Autoradiography; D001798:Blood Proteins / Q000378:metabolism*; D050071:Bone Density Conservation Agents / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D004164:Diphosphonates / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D004285:Dogs; D005243:Feces; D007093:Imidazoles / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D008297:Male; D011485:Protein Binding; D051381:Rats; D012680:Sensitivity and Specificity; D014018:Tissue Distribution; D000077211:Zoledronic Acid
chemical_list: D001798:Blood Proteins; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid