Chemical formula: C₁₃H₈F₂O₃ Molecular mass: 250.198 g/mol PubChem compound: 3059
Diflunisal is a potent stabiliser of tetrameric transthyretin (TTR), which effectively stabilises the tetramer against dissociation to the TTR monomers which are responsible for amyloidosis pathology.
Diflunisal is close to completely absorbed when used in therapeutic doses. Peak plasma concentrations occur within 2 to 3 hours. Food affects the rate of diflunisal absorption but not the extent of absorption.
The degree of protein binding in plasma is high; approximately 98-99% of diflunisal in plasma is bound to proteins.
At the clinical dose of 250 mg twice daily, steady state concentrations of diflunisal in plasma are reached after 4-5 days and the plasma elimination half-life of diflunisal is 8-10 hours. At higher repeated twice daily doses of diflunisal, time to steady state concentrations of diflunisal and plasma elimination half-life are increased dose-proportionately.
No metabolites of diflunisal have been identified in human plasma. Diflunisal is extensively metabolised mainly in the liver by phase 2 conjugation enzymes and its conjugates have been identified in urine.
In humans, diflunisal is mainly metabolised to form two glucuronide conjugates and one sulphate conjugate, which are water soluble and excreted in the urine. Diflunisal is also excreted in smaller amounts in the urine, approximately 5% of dose administered. Age, weight, gender and ethnicity are not expected to have a significant effect on elimination of diflunisal.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential, which is additional to those already mentioned in other sections of this Summary of Product Characteristics. However, based on doses/human equivalent doses, exposures at the No Observed Adverse Effect Levels (NOAEL) in the different studies were only slightly higher or even below those in patients receiving the maximum recommended human dose.
Diflunisal has shown no evidence of effects on fertility in rats but has been shown to increase the length of the gestation period in rats. Diflunisal has shown no evidence of developmental toxicity in mice, rats and cynomolgus monkeys. Severe maternal haemolytic anaemia was uniquely induced in rabbits, resulting in developmental toxicities in foetuses.
Data suggest that diflunisal is more toxic to neonatal rats and dogs than to adult animals.
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