Pharmacokinetics of latanoprost in the cynomolgus monkey - 3rd Communication: Tissue distribution after topical administration on the eye studied by whole body autoradiography

Latanoprost (13,14-dihydro-15(R)-17-phenyl-18,19,20-trinor-PGF(2a)-isopropy l ester, CAS 130209-82-4, PhXA41, Xalatan(R)), an antiglaucoma drug, labell ed with tritium at carbon 13 and 14 (4.8 mu g, 20.8 MBq/eye) was administer ed topically on the eyes of cynomolgus monkeys. After 0.5 h the concentrati on of radioactivity in the cornea was estimated to be about 0.6 ng eq/mg ti ssue. The elimination half-life of total radioactivity in the cornea was ab out 4 h. The corneal epithelium contained a higher concentration of radioac tivity than the stroma. Cornea seemed to act as a slow release depot to the anterior part of the eye. In the his, anterior chamber and ciliary body th e maximal concentrations were 217.0 +/- 12.9 pg eq/mg, 99.8 +/- 7.4 pg eq/m g and 54.0 +/- 4.9 pg eq/mg, respectively, 1 h after administration. The el imination half-life of total radioactivity from these tissues was 3-4 h. Tr ace amounts (0.4-9 pg eq/mg) remained in these tissues 24 h after administr ation. Initially the radioactivity was present in the conjunctiva, sclera a nd choroid as well as in the general circulation. Radioactivity passed thro ugh the lachrymal ducts and high concentrations were observed in the oesoph agus, stomach content, small intestine, bile and urine of a monkey administ ered latanoprost topical on the eye 0.5 and 1 h before sacrifice. In this a nimal concentrations of radioactivity were found in the kidney liver, wall of the small intestine and blood. All other tissues in this animal containe d lower concentrations of radioiactivity than the blood. In an animal sacri ficed 2 h after administration of tritium labelled latanoprost on one eye a nd 6 h after administration on the other eye the highest concentrations of radioactivity were found in urine, bile and in the stomach content. Low con centration of radioactivity remained in the kidney and the liver. III a mon key administered latanoprost 12 and 24 h before death low concentrations re mained in the colon, bile and urine. The anterior parts of the eyes from the monkey sacrificed 0.5 and 1 h after administration of latanoprost were cut out from the tissue sections for HP LC analysis. The predominating peak present corresponded to acid of latanop rost (PhXA85). In the stomach the radioactivity chromatographed as latanopr ost and the acid of latanoprost. In the small intestine and in bile the mai n radioactive peak corresponded to 1.2-dinor-acid of latanoprost and in add ition several more polar metabolites were present. In conclusion, latanoprost penetrated the cornea, was hydrolysed and slowly released into the anterior parts of the eye, the site of action. The maxim um concentration in the eye was reached after 1 h with an elimination half- life of 3-4 h. In the body the distribution was limited mainly to the gastr o-intestinal tract? the kidney the gall- and urinary bladder.