ジクロロメチレンビス(ホスホン酸)

250

250 °C

The bisphosphonate group binds strongly to the bone mineral, hydroxyapatite. This explains the specific pharmacological action of these compounds on mineralized tissues, especially bone. The exact mechanism of action of clodronate is not known, however it is known that it does not inhibit protein isoprenylation but can be metabolized intracellularly to a &beta;-&gamma;-methylene (AppCp-type) analog of ATP (AppCCl2p), which is cytotoxic to macrophages in vitro. Inhibition of the ADP/ATP translocase by the metabolite AppCCl2p is a likely route by which clodronate causes osteoclast apoptosis and inhibits bone resorption. Recently, the slime mold <i>Dictyostelium discoideum</i> was shown to take up bisphosphonates by pinocytosis. In these cells, clodronate, but not other pharmacologically active bisphosphonates, was incorporated into adenine nucleotides, which could potentially explain why this bisphosphonate sometimes seems to act differently than the other bisphosphonates. Clodronate, like all biphosphonates, also binds protein-tyrosine-phosphatase.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

Clodronic acid

DILI Positive

DOI:10.1016/j.drudis.2019.09.022

M05BA02

M - Musculo-skeletal system；M05 - Drugs for treatment of bone diseases；M05B - Drugs affecting bone structure and mineralization；M05BA - Bisphosphonates；M05BA02 - Clodronic acid

QM - Musculo-skeletal system；QM05 - Drugs for treatment of bone diseases；QM05B - Drugs affecting bone structure and mineralization；QM05BA - Bisphosphonates；QM05BA02 - Clodronic acid

Clodronic acid is a first generation bisphosphonate that inhibits osteoclast mediated bone resorption. It has a wide therapeutic index as a large overdose is required for significant toxicity and a long duration of action due to the slow release from bone. Patients should be counselled regarding the risk of hypocalcemia, hypovolemia, renal insufficiency, transient hyperphosphatemia, and transient hyperparathyroidism.

Bisphosphonates are taken into the bone where they bind to hydroxyapatite. Bone resorption by osteoclasts causes local acidification, releasing the bisphosphonate, which is taken into the osteoclast by fluid-phase endocytosis. Endocytic vesicles become acidified, releasing bisphosphonates into the cytosol of osteoclasts where they act. Osteoclasts mediate resorption of bone. When osteoclasts bind to bone they form podosomes, ring structures of F-actin. Disruption of the podosomes causes osteoclasts to detach from bones, preventing bone resorption. First generation bisphosphonates closely mimic the structure of pyrophosphate, which can be incorporated into ATP anologues that cannot be hydrolyzed, disrupting all ATP mediated actions of osteoclasts.

Clodronate is not metabolized in humans.

Clodronate is not metabolized in humans. It can be metabolized intracellularly to a beta-gamma-methylene (AppCp-type) analog of ATP (AppCCl2p), which is cytotoxic to macrophages in vitro. Half Life: Approximately 13 hours.

Oral clodronic acid has a bioavailability of 1-2%. A 200mg intravenous dose reaches a Cmax of 16.1mg/L with an AUC of 44.2mg\*h/L. A 200mg intramuscular dose reaches a Cmax of 12.8mg/L with an AUC of 47.5mg\*h/L. Further pharmacokinetic data for clodronic acid are not readily available.

Clodronate is eliminated unchanged in the urine.

The renal clearance of clodronate is approximately 90mL/min.

Use (kg; approx.) in Germany (2009): >500；Consumption (g per capita; approx.) in Germany (2009): 0.00611；Calculated removal (%): 8.8

A diphosphonate which affects calcium metabolism. It inhibits bone resorption and soft tissue calcification. For the management of hypercalcemia of malignancy and as an adjunct in the management of osteolysis resulting from bone metastases of malignant tumors.