Received for publication November 13, 2008.
Revised May 22, 2009.
Accepted for publication May 26, 2009.

Disposition and Metabolism of a Novel Prostanoid Antiglaucoma Medication, Tafluprost, Following Ocular Administration to Rats

Abstract

The disposition and metabolism of tafluprost, an ester prodrug of the 15,15-difluoro-PGF₂ antiglaucoma agent, have been studied in rats after ocular administration. Radioactivity was absorbed very rapidly into the eye and systemic circulation after a single ocular dose of 0.005% [³H]tafluprost ophthalmic solution, with maximum levels in plasma and most eye tissues occurring within 15 minutes. The absorption ratio of radioactivity was about 75%, suggesting the high availability of ocular administration of tafluprost. About 10% of the dose was present in cornea at this time, and radioactivity concentrations in this tissue exceeded those in aqueous humour and iris/ciliary body throughout the 24-hour study period. After repeated daily ocular doses, radioactivity levels remained greatest in cornea, followed by iris/ciliary body that replaced aqueous humour as the eye tissue containing the second highest radioactivity concentration. In female rats, radioactivity was excreted equally between urine and faeces after a single ocular dose, whereas in males more was excreted in faeces, reflecting the greater biliary excretion in males (50% dose) compared with females (33% dose). Tafluprost was extensively metabolised in the rat, such that intact prodrug was not detected in plasma, tissues or excreta by radio-HPLC. On the other hand, the active moiety, tafluprost acid, was the only noteworthy radioactive component in cornea, aqueous humour and iris/ciliary body for at least 8 h after the ocular dose, and was also a major plasma metabolite in early time points. The gender differences in conjugation reactions resulted in the differences in the excretion.

Key words: distribution, drug development, drug disposition, metabolite identification, prodrugs, prostaglandins, structure elucidation