Disposition of tiludronate (Skelid) in animals

Abstract

The disposition of tiludronate in mouse, rat, rabbit, dog and monkey has been studied after oral and intravenous doses. Like other bisphosphonates, tiludronate was characterized by poor absorption from the gastrointestinal tract. Peak plasma concentrations appeared shortly (0.5-1 h) after dosing, except for the baboon (4.5 h). Food intake highly impaired intestinal absorption The affinity of tiludronate for bone and the slow release from this deep compartment could account for the large volume of distribution and the low plasma clearance found in all species. Tiludronate has low affinity for red blood cells and binds moderately to serum proteins, mainly to serum albumin. Calcified tissues appeared to be the main target for deposition. Distribution into bone was not homogenous, with higher levels in the trabecular bone than in the corticol part of the long bones. The uptake of tiludronate into bone was unequivocally less in the older animal. No metabolism occurred in the tested animal species. The major route of elimination of the absorbed drug is urine. Preclinical observations made with tiludronate, like with other bisphosphonates, were predictive of results obtained in clinical investigation.

Reduction of instability-induced bone resorption using bisphosphonates: High doses are needed in rats

“…Some data show that the distribution of bisphosphonates to bone is not homogeneous (Davi et al 1999). Bisphosphonates bind preferentially to regions with higher turnover of bone, such as the trabecular bone in the proximal tibia in rats, as opposed to the cortical bone in the same region.…”

Synthesis and Functionalization of 5‐Substituted Tetrazoles

“…From the point of view of the pharmacodynamics, the effect of the replacement of a carboxylic acid by a 5-ST is more complex. During the administration of compound AA-344 [6-ethyl-3-(1H-tetrazol-5-yl)chromone] to laboratory animals the N1 isomer was primarily found, [18] whereas the group of compounds derived from 5-(biphenyl-2-yl)-1H-tetrazoles (antagonists of the receptor for angiotensin II) [19] or the potential antidiabetic drug RG 12525 {2-[(4-{[2-(1H-tetrazol-5-ylmethyl)phenyl]meth-oxy}phenoxy)methyl]quinoline} [20] were predominantly metabolized to the N2 isomers. [12] The size of the tetrazole ring might decrease the affinity towards the receptor site relative to a carboxylate group as a result either of steric hindrance or of an inconvenient orientation of the functional groups of the active site.…”

“…The delocalization of the negative charge in the tetrazole ring can either enhance or reduce the interaction with an appropriate receptor, depending on the electron distribution in the receptor site. [19] The most important group of biologically active compounds based on 5-STs are the selective antagonists of the receptor for angiotensin II. [13] The main difference between the carboxylate and the tetrazole anion lies in the ability of all of the nitrogen atoms, which act as acceptors of hydrogen bonds, to interact with a receptor.…”

Effect of dodecylmaltoside (DDM) on uptake of BCS III compounds, tiludronate and cromolyn, in Caco-2 cells and rat intestine model

“…Tiludronate is a bisphosphonate compound used for bone-related disorders (Davi et al, 1999) characterized by extremely poor and variable oral absorption. Cromolyn is prescribed for treatment of bronchial asthma and allergic rhinitis, with oral bioavailability less than 5% (Leone-Bay et al, 1996).…”