Received for publication February 19, 2008.
Revised July 10, 2008.
Accepted for publication July 10, 2008.

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, ¹⁴C-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 non-calcified tissues was investigated up to 240 days in rats and 96 hours 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 non-calcified tissue but only a slow decline in bone, to 50% of peak at 240 days post dose, whereas the terminal half-lives (50-200 days) were similar in bone and non-calcified 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 post dose, the fraction of dose excreted was 36% in rat and 60% in dog; 94-96% of the excreted radioactivity was found in urine. Blood/plasma concentration ratios were 0.52-0.59 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 non-calcified tissue is governed by extensive uptake into and slow release from bone.

Key words: anticancer agents, drug distribution, plasma protein binding, renal elimination