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Latanoprost (13,14-dihydro-15(R)-17-phenyl-18,19,20-trinor-PGF2a isopropyl ester, CAS 130209-82-4 PhXA41, Xalatan) is an antiglaucoma prodrug which enhances the bioavailability of the drug into the eye compared to the corresponding acid. The pharmacokinetics and metabolism of this drug was studied in the cynomolgus monkey after daily topical administration on the eye of [13,14-(3) H] labelled latanoprost (6 micrograms per eye) during 21 days. Plasma, urine and homogenised faeces samples were purified by separation on a Sep-Pak C18 cartridge before analysis by reversed phase liquid chromatography (RP-HPLC) with one-line radioactivity detection. The maximum plasma concentration of radioactivity obtained within 10 min post dose was as a mean 7.87 +/- 3.18 ng eq./ml on day 1 and 9.31 +/- 4.21 ng eq./ml on day 21. The plasma concentration of radioactivity declined rapidly up to 3 h post-dose both on day 1 and day 21, but a small amount of tritiated water accumulated with time. The majority of the radioactivity was recovered in urine but substantial amounts were also eliminated in the faces. No latanoprost was found in plasma after repeated topical administration on the eye. The plasma profiles from HPLC separation of samples showed a rapid and complete hydrolysis of the ester. The elimination half-life of the acid of latanoprost was estimated to be 13.8 +/- 1.7 min for day 1 and 12.4 +/- 4.8 min for day 21. No induction or inhibition of the metabolism occurred after the repeated administration. By comparison with reference substances the 15-keto acid of latanoprost was found to be present in plasma and the major metabolites in urine and faeces collected during day 2 and day 20 were identified as 1,2-dinor acid of latanoprost, 1,2,3,4-tetranor acid and 1,2,3,4-tetranor lactone of latanoprost. Tritiated water was excreted in the urine and a small amount of the acid of latanoprost was excreted in the faeces. In conclusion, latanoprost was rapidly absorbed and hydrolysed to the corresponding acid after repeated topical administration to the monkey eye. The acid of latanoprost had a short half-life in plasma and it was partly converted to the 15-keto acid of latanoprost. beta-Oxidation of the acid of latanoprost was the major metabolic pathway. No induction or inhibition of the metabolism occurred upon repeated administration and no indications of accumulation of the drug or drug metabolites were observed. The pharmacokinetics of latanoprost was similar after a single and repeated topical administration.

Latanoprost (13,14-dihydro-17-phenyl-18,19,20-trinor-prostaglandin F2alpha-1-isopropyl ester) is a unique prostaglandin analogue developed for the treatment of glaucoma. To investigate the pharmacokinetics, tritium-labeled latanoprost was administered topically on the eyes of rabbits and intravenously. About 7.7% of the applied dose was found in the cornea at 15 min after the drug administration. The following Cmax and elimination half-life (interval 1-6 hr) values of the total radioactivity in the eye tissues were found: aqueous humor, 0.09 ng eq/ml and 3.0 hr; anterior sclera, 1.49 ng eq/mg and 1.8 hr; cornea, 1.59 ng eq/mg and 1.8 hr; ciliary body, 0.39 ng eq/mg and 2.8 hr; conjunctiva, 1.41 ng eq/mg and 1.4 hr; and iris, 0.39 ng eq/mg and 2.1 hr. Latanoprost was rapidly hydrolyzed, and most of the radioactivity found in the aqueous humor, anterior eye tissues, and plasma corresponded to the pharmacologically active acid of latanoprost. The initial plasma elimination half-life of the acid of latanoprost was 9.2 +/- 3.2 min after iv and 2.3 +/- 1.9 min after topical administration on the eyes. The plasma clearance of the acid of latanoprost was 1.8 +/- 0.3 liters/hr.kg, and the volume of distribution was 0.4 +/- 0.1 liter/kg after iv administration. Based on the retention times on HPLC and GC-MS, the main metabolite in urine and feces was identified as the 1,2,3,4-tetranor metabolite of acid of latanoprost. This acid existed in equilibration with the corresponding delta-lactone. The AUC of radioactivity in the eye tissues was approximately 1000 times higher than in plasma AUC. The recovery of radioactivity was complete.