Diquas/Diquas-S Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of action: Diquafosol sodium stimulated water and mucin secretion by acting on P2Y₂ receptors on the conjunctival epithelial and goblet cell membrane and elevating intracellular calcium ion concentrations.
Stimulatory action on secretion of tear fluid including mucin: A single dose administration of diquafosol sodium into the eyes of normal animals (rabbits and rats) promoted tear fluid secretion and mucin secretion from the conjunctival cells.
A single dose administration of diquafosol sodium into the eyes of dry eye model rats promoted tear fluid secretion. Repeated dose administration increased mucin contents in the conjunctival tissues.
Stimulatory action on mucin production in corneal epithelial cells: Diquafosol sodium stimulated gene expression and protein production of membrane-associated mucin in corneal epithelial cells.
Improvement of corneal epithelial damage: Repeated dose administration of diquafosol sodium 6 times daily for 4 weeks improved corneal epithelial damage in rat dry eye model in a dose-dependent manner, and exhibited the maximal effect at the concentration of 1% or higher. Repeated dose of 1% diquafosol sodium for 2 weeks exhibited the maximal improvement effect when daily administration exceeded 6 times.
Pharmacokinetics: Plasma concentrations: After topical administration of diquafosol sodium solution either at concentrations of 0.3%, 1%, 3% or 5% to the eye of healthy adult volunteers one drop, once daily for one day, 6 times daily for one day or 6 times daily for 7 days, the plasma concentrations of diquafosol sodium and its metabolites were measured. Those of diquafosol sodium were below the lower limit of quantitation (2ng/mL) at every time point in all of the volunteers. The plasma concentration of metabolites (UTP, UDP, UMP and uridine) did not affect physiological concentrations derived from the endogenous components.
(Note: The approved concentration of this product is 3%.)
Ocular tissue distribution in animals: (Rabbits): Following a single topical administration of 3% ¹⁴C-diquafosol sodium ophthalmic solution to rabbit eyes, the radioactivity was distributed in the extraocular tissues including the conjunctiva and cornea, and reached the maximum radioactive concentrations in the cornea and conjunctiva at 5 minutes after administration. Thereafter, the radioactivity reduced to 4 to 30% of the maximum concentrations at 24 hours after administration.
Metabolism: (Human in vitro): In vitro metabolism reaction using human plasma and human liver microsome demonstrated that diquafosol sodium was rapidly metabolized, and UMP, uridine and uracil were produced.
(Rabbits): At 30 minutes after instillation of 3% ¹⁴C-diquafosol sodium ophthalmic solution to rabbit eyes, diquafosol sodium was hardly detected in the ocular tissues, and instead UTP, UDP, UMP, uridine and uracil were detected.