チルドロン酸

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

tiludronate

DILI Negative

Oral

DOI:10.1016/j.drudis.2019.09.022

M - Musculo-skeletal system

QM - Musculo-skeletal system

Tiludronic acid is a bisphosphonate that prevents osteoclasts from resorbing bone. The duration of action is quite long due to the slow clearance from the bone, and the therapeutic window is wide. Patients should be counselled regarding the risk of upper GI mucosal irritation as well as gastric and duodenal ulcers.

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. Tiludronate inhibits protein-tyrosine-phosphatase, which increases tyrosine phosphorylation, and disrupts podosome formation. Tiludronic acid also inhibits V-ATPases in the osteoclast, though the exact subunits are unknown, preventing F-actin from forming podosomes. Disruption of the podosomes causes osteoclasts to detach from bones, preventing bone resorption.

6PNS59HP4Y

TILUDRONIC ACID

Established Pharmacologic Class [EPC] - Bisphosphonate

Chemical Structure [CS] - Diphosphonates

Tiludronic acid is a Bisphosphonate.

A single 400mg dose of tiludronic acid reaches a Cmax of 3.35±1.07mg/L, with a Tmax of 1.7—0.9h, and and AUC of 27.2±9.0mg\*h/L. Tiludronic acid has an oral bioavailability of 2-11% with an average of 6%.

Tiludronic acid is 60% eliminated in the urine as the unchanged parent drug.

The volume of distribution of tiludronic acid is estimated to be between 30L and 60L. Due to the unknown clearance rate from bone, this may underestimate the true volume of distribution.

Tiludronic acid has a renal clearance of 0.68L/h in healthy subjects and 0.47L/h in subjects with Paget's disease. Approximately 50% of tilurdronic acid binds to bone but the rate of clearance from the bone is unknown.