title: 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-prostaglandin F(2alpha) 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% [(3)H]tafluprost ophthalmic solution, with maximum levels in plasma and most eye tissues occurring within 15 min. The absorption ratio of radioactivity was approximately 75%, suggesting the high availability of ocular administration of tafluprost. Approximately 10% of the dose was present in cornea at this time, and radioactivity concentrations in this tissue exceeded those in aqueous humor and iris/ciliary body throughout the 24-h study period. After repeated daily ocular doses, radioactivity levels remained greatest in cornea, followed by iris/ciliary body that replaced aqueous humor as the eye tissue containing the second highest radioactivity concentration. In female rats, radioactivity was excreted equally between urine and feces after a single ocular dose, whereas in male rats more was excreted in feces, reflecting the greater biliary excretion in males rats (50% dose) compared with females rats (33% dose). Tafluprost was extensively metabolized in the rat, such that intact prodrug was not detected in plasma, tissues, or excreta by radio-high-performance liquid chromatography. On the other hand, the active moiety, tafluprost acid, was the only noteworthy radioactive component in cornea, aqueous humor, and iris/ciliary body for at least 8 h after the ocular dose, and it was also a major plasma metabolite in early time points. The gender differences in conjugation reactions resulted in the differences in the excretion.
authors.affiliation: Non-clinical Research Group, Research and Development Center, Santen Pharmaceutical Co. Ltd., 8916-16 Takayama-cho, Ikoma-shi, Nara, Japan. yasufumi.fukano@santen.co.jp
authors.forename: Y
authors.initials: Y
authors.lastname: Fukano
authors.forename: K
authors.initials: K
authors.lastname: Kawazu
mesh_terms: D000287:Administration, Topical; D000818:Animals; D001682:Biological Availability; D001711:Biotransformation; D002853:Chromatography, Liquid; D004285:Dogs; D005123:Eye / Q000378:metabolism*; D005243:Feces / Q000737:chemistry; D005260:Female; D005901:Glaucoma / Q000188:drug therapy*; D020719:Glucuronides / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D007275:Injections, Intravenous; D007774:Lactation; D008252:Macaca fascicularis; D008297:Male; D055432:Metabolomics / Q000379:methods; D008892:Milk / Q000378:metabolism; D009883:Ophthalmic Solutions; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011355:Prodrugs / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D011460:Prostaglandins F / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution; D014316:Tritium
chemical_list: D020719:Glucuronides; D009883:Ophthalmic Solutions; D011355:Prodrugs; D011460:Prostaglandins F; D014316:Tritium; C485333:tafluprost