Zinvel Mechanism of Action

Pharmacology: Mechanism of Action: Zoledronic Acid inhibits bone resorption by altering osteoclast activity and by inhibiting normal endogenous, as well as tumor induced, mediators of bone degradation. Like other bisphosphonates, Zoledronic Acid binds to hydroxyapatite crystals in mineralized bone matrix. The binding to calcium phosphates slows the dissolution of hydroxyapatite crystals, as well as inhibits the formation and aggregation of these crystals. Zoledronic Acid is incorporated into osteoclastic bone surfaces, where it inhibits bone resorption by inhibiting osteoclastic activity and inducing osteoclastic apoptosis. The presence of bisphosphonates in the bone structure appears to prevent acid extrusion, an important step stimulated by osteoclasts during the bone resorption process.
Following subsequent resorption, bone tissue surrounding the bisphosphonate containing bone tends to lack ruffled borders and has fewer vacuoles, which are changes consistent with lower resorptive capacity, therefore osteoclasts may be inhibited not only when bisphosphonates are directly incorporated into the bone matrix, but after they engulf bisphosphonate containing mineral during active resorption as well.
Zoledronic Acid affects chemical and hormonal mediators of bone degradation. Zoledronic Acid inhibits the increased osteoclastic activity and skeletal calcium release induced by various stimulatory factors released by tumors. This may be due to mediation of release of interleukin (IL-1 beta, IL-6 and tumour necrosis factor (TNF)) by monocytes. These cytokines are involved in osteoclast recruitment and activation. Zoledronic Acid appears to have direct antitumour effects in specific types of cancer cells. Although the exact mechanism is not known. Zoledronic Acid has been demonstrated to inhibit cell growth and induce apoptosis in human myeloma, breast cancer and prostate cancer cell lines.
Pharmacokinetics: Zoledronic Acid is administered by intravenous infusion. Human oral absorption data for Zoledronic Acid are unavailable. Other bisphosphonates are poorly absorbed (e.g. less than 5% of a dose for alendronate, tiludronate, etidronate) and absorption is further retarded by administration with food or calcium or other divalent cations. After intravenous infusion, zoledronic acid distributes primarily to bone in a triphasic process. It does not inhibit P450 enzymes in vitro. Zoledronic Acid plasma concentrations are dose proportional. Plasma protein binding is approximately 22% and independent of Zoledronic Acid concentrations. More than 95% of Zoledronic Acid is excreted unchanged, via the kidney. The elimination is triphasic with and alpha early distribution half life of 0.23 hrs, a beta half life of 1.75 hrs and terminal elimination half life of 167 hrs with low plasma concentrations observed up to 28 days post dose.