Pharmacokinetics of latanoprost in the cynomolgus monkey - 1st Communication: Single intravenous, oral or topical administration on the eye

Latanoprost (13,14-dihydro-15(R)-17-phenyl-18,19,20-trinor-PGF(2a)- isoprop yl eater, CAS 130209-82-4 PhXA41, Xalatan(R)) is a prodrug used for reducti on of the intraocular pressure in the treatment of glaucoma. The pahrmacoki netics of this drug was studied in the cynomolgus monkey after intravenous, oral and topical administration of 9 beta-[H-3] labelled latanoprost. The plasma profile of radioactivity from HPLC separation of samples obtained af ter intravenous as well as topical administration on the eyes showed a rapi d and complete hydrolysis of the ester. The pharmacologically active acid o f latanoprost showed a maximum concentration 5 min post topical administrat ion and an elimination half-life of about 10 min. Tertiary butyldimethylsil yl derivatives were prepared of the radioactive fractions collected from th e HPLC column. The derivatives were analysed by gas chromatography-mass spe ctrometry (GC-MS). After oral administration no latanoprost and very little of its acid was present in plasma, indicating a first-pass metabolism resu lting in more polar compounds. Based on the retention times on the HPLC and GC and on a mass spectrum simi lar to the acid of latanoprost but 28 daltons lower, the main metabolite in urine and faeces was identified as the 1,2-dinor acid of latanoprost. In a similar way a more polar fraction from urine was identified as the 1,2,3,4 -tetranor metabolite of the acid of latanoprost. The tissue distribution after i.v. and topical administration was similar w ith organs of metabolism (liver) and elimination (kidney) containing the hi ghest concentrations. After topical application much of the dose was found in the anterior ocular tissues but not in the posterior parts of the eye. In conclusion, latanoprost is a prodrug which in vivo rapidly is hydrolysed to the corresponding free acid. The acid of latanoprost has a short half-l ife in plasma and is extensively metabolised mainly through beta-oxidation before it is excreted into the urine and faeces.