Pharmacokinetics of latanoprost in the cynomolgus monkey - 2nd Communication: Repeated topical administration on the eye

Latanoprost (13,14-dihydro-15(R)-17-phenyl-18,19,20-trinor-PGF(2a) isopropy l ester, CAS 130209-82-4 PhXA41, Xalatan(R)) is an antiglaucoma prodrug whi ch enhances the bioavailability of the drug into the eye compared to the co rresponding acid. The pharmacokinetics and metabolism of this drug was stud ied in the cynomolgus monkey after daily topical administration on the eye of [13,14-H-3] labelled latanoprost (6 mu g per eye) during 21 days. Plasma , urine and homogenised faeces samples were purified by separation on a Sep -Pak C-18 cartridge before analysis by reversed phase liquid chromatography (RP-HPLC) with one-line radioactivity detection. The maximum plasma concen tration of radioactivity obtained within 10 min post dose was as a mean 7.8 7 +/- 3.18 ng eq./ml on day and 9.31 +/- 4.21 ng eq./ml on day 21. The plas ma 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 wit h time. The majority of the radioactivity was recovered in urine but substa ntial amounts were also eliminated in the faeces. No latanoprost was found in plasma after repeated topical administration on the eye. The plasma prof iles from HPLC separation of samples showed a rapid and complete hydrolysis of the ester. The elimination half-life of the acid of latanoprost was est imated 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 admi nistration. By comparison with reference substances the 15-keto acid of lat anoprost was found to be present in plasma and the major metabolites in uri ne and faeces collected during day 2 and day 20 were identified as 1,2-dino r acid of latanoprost, 1,2,3,4-tetranor acid and 1,2,3,4-tetranor lactone o f 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 corre sponding acid after repeated topical administration to the monkey eye. The acid of latanoprost had a short half-life in plasma and it was partly conve rted to the 15-keto acid of latanoprost. P-Oxidation of the acid of latanop rost was the major metabolic pathway. No induction or inhibition of the met abolism occurred upon repeated administration and no indications of accumul ation of the drug or drug metabolites were observed. The pharmacokinetics o f latanoprost was similar after a single and repeated topical administratio n.