Description
Zoledronic acid is a white, crystalline powder that is available in vials for reconstitution for IV infusion over at
least 15 minutes. It does not undergo metabolic transformation and does not inhibit CYP450 enzymes.
Clearance of this agent is dependent on the patient's creatinine clearance, not on dose. Serum creatinine
levels should be evaluated before every treatment. Zolendronic acid is contraindicated in patients with severe
renal impairment.
Chemical Properties
White Solid
Originator
Zometa,Novartis Pharma,Switz
Uses
Bisphosphonate antiresorptive agent
Uses
bone resorption inhibitor
Definition
ChEBI: An imidazole compound having a 2,2-bis(phosphono)-2-hydroxyethane-1-yl substituent at the 1-position.
Manufacturing Process
With stirring and under reflux, 8.6 g (0.053 mole) of imidazol-4-yl acetic acid
hydrochloride, 7.1 ml of 85% phosphoric acid and 25 ml of chlorobenzene are
heated to 100°C. Then 13.9 ml of phosphorus trichloride are added dropwise
at 100°C, whereupon evolution of gas occurs. Over the course of 30 min a
dense mass precipitates from the reaction mixture. The batch is heated for 3
hours to 100°C and the supernatant chlorobenzene is removed by
decantation. With stirring and under reflux, the residual viscous mass is
heated to the boil for 3 hours with 40 ml of 9 N hydrochloric acid. The batch
is filtered hot with the addition of carbon and the filtrate is diluted with
acetone, whereupon the crude 2-(imidazol-4-yl)-1-hydroxy-ethane-1,1-
diphosphonic acid precipitates. This product is recrystallised from water.
Melting point: 238-240°C (dec.).
Brand name
Zometa (Novartis).
Therapeutic Function
Bone calcium regulator
Biological Functions
Zoledronic acid, a bisphosphonate, was approved by the U.S. FDA in 2001 for the treatment of hypercalcemia
of malignancy, a metabolic complication that can be life-threatening. Hypercalcemia of malignancy
can occur in up to 50% of patients diagnosed with advanced breast cancer, multiple myeloma, and nonsmall
cell lung cancer. This condition arises when chemical moieties produced by the tumor cause overstimulation of
osteoclasts. When there is an increase in bone degradation, there is a concomitant release of calcium into the
plasma. When serum concentrations of calcium rapidly elevate, the kidneys are unable to handle the overload,
and hypercalcemia results. This can lead to dehydration, nausea, vomiting, fatigue, and confusion. Zoledronic
acid effectively decreases plasma calcium concentrations via inhibition of bone resorption (inhibition of
osteoclastic activity and induction of osteoclast apoptosis). It also prevents the increase in osteoclastic activity
caused by tumor-based stimulatory factors. Additionally zoledronic acid has been approved by the U.S. FDA for
the treatment of multiple myeloma and bone metastases associated with solid tumor–based cancers (e.g.,
prostrate and lung). This agent is currently in late-stage clinical trials for the treatment and prevention of
osteoporosis and, if approved, will be formulated as a 5-mg, once-yearly IV infusion.
Clinical Use
Zoledronic acid is most
commonly given to patients whose cancer is no longer responding to hormones, but it also may be
given to prevent the bone thinning and weakening that results from hormonal treatments.
Drug interactions
Potentially hazardous interactions with other drugs
Other nephrotoxic drugs: use with caution as can
enhance nephrotoxicity
Metabolism
Zoledronic acid is not metabolised and is excreted unchanged via the kidney. Over the first 24 hours, 39 ± 16
% of the administered dose is recovered in the urine, while the remainder is principally bound to bone tissue.
References
1) Green?et al. (1994),?Preclinical pharmacology of CGP 42446, a new, potent, heterocyclic bisphosphonate compound; J. Bone Miner. Res.,?9?745
2) Deeks and Perry (2008)?Zoledronic acid: a review of its use in the treatment of osteoporosis; Drugs Aging,?25?963
3) Perry and Figgitt (2004),?Zoledronic acid: a review of its use in patients with advanced cancer; Drugs,?64?1197
4) Koto?et al. (2010)?Zoledronic acid inhibits proliferation of human fibrosarcoma cells with induction of apoptosis and shows combined effects with other anticancer agents; Oncol. Rep.,?24?233
5) Tonyali?et al. (2010)?The role of zoledronic acid in the adjuvant treatment of breast cancer: current perspectives; Expert Opin. Pharmacother.,?11?2715
