Pharmacokinetics of latanoprost in the cynomolgus monkey. 3rd communication: tissue distribution after topical administration on the eye studied by whole body autoradiography. Glaucoma Research Laboratories.

摘要

Latanoprost (13,14-dihydro-15(R)-17-phenyl-18,19,20-trinor-PGF2 alpha-isopropyl ester, CAS 130209-82-4, PhXA41, Xalatan), an antiglaucoma drug, labelled with tritium at carbon 13 and 14 (4.8 micrograms, 20.8 MBq/eye) was administered topically on the eyes of cynomolgus monkeys. After 0.5 h the concentration of radioactivity in the cornea was estimated to be about 0.6 ng eq/mg tissue. The elimination half-life of total radioactivity in the cornea was about 4 h. The corneal epithelium contained a higher concentration of radioactivity than the stroma. Cornea seemed to act as a slow release depot to the anterior part of the eye. In the iris, anterior chamber and ciliary body the maximal concentrations were 217.0 +/- 12.9 pg eq/mg, 99.8 +/- 7.4 pg eq/mg and 54.0 +/- 4.9 pg eq/mg, respectively, 1 h after administration. The elimination half-life of total radioactivity from these tissues was 3-4 h. Trace amounts (0.4-9 pg eq/mg) remained in these tissues 24 h after administration. Initially the radioactivity was present in the conjunctiva, sclera and choroid as well as in the general circulation. Radioactivity passed through the lachrymal ducts and high concentrations were observed in the oesophagus, stomach content, small intestine, bile and urine of a monkey administered latanoprost topical on the eye 0.5 and 1 h before sacrifice. In this animal concentrations of radioactivity were found in the kidney, liver, wall of the small intestine and blood. All other tissues in this animal contained lower concentrations of radioiactivity than the blood. In an animal sacrificed 2 h after administration of tritium labelled latanoprost on one eye and 6 h after administration on the other eye the highest concentrations of radioactivity were found in urine, bile and in the stomach content. Low concentration of radioactivity remained in the kidney and the liver. In a monkey administered latanoprost 12 and 24 h before death low concentrations remained 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 HPLC analysis. The predominating peak present corresponded to acid of latanoprost (PhXA85). In the stomach the radioactivity chromatographed as latanoprost and the acid of latanoprost. In the small intestine and in bile the main radioactive peak corresponded to 1,2-dinor-acid of latanoprost and in addition 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 maximum 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 gastro-intestinal tract, the kidney, the gall- and urinary bladder.