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-PGF2a- isopropyl ester, CAS 130209-82-4 PhXA41, Xalatan) is a prodrug used for reduction of the intraocular pressure in the treatment of glaucoma. The pahrmacokinetics of this drug was studied in the cynomolgus monkey after intravenous, oral and topical administration of 9 beta-[3H] labelled latanoprost. The plasma profile of radioactivity from HPLC separation of samples obtained after intravenous as well as topical administration on the eyes showed a rapid and complete hydrolysis of the ester. The pharmacologically active acid of latanoprost showed a maximum concentration 5 min post topical administration and an elimination half-life of about 10 min. Tertiary butyldimethylsilyl derivatives were prepared of the radioactive fractions collected from the HPLC column. The derivatives were analysed by gas chromatography-mass spectrometry (GC-MS). After oral administration no latanoprost and very little of its acid was present in plasma, indicating a first-pass metabolism resulting in more polar compounds. Based on the retention times on the HPLC and GC and on a mass spectrum similar 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 with organs of metabolism (liver) and elimination (kidney) containing the highest 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-life in plasma and is extensively metabolised mainly through beta-oxidation before it is excreted into the urine and faeces.
Sjöquist
B
B
Glaucoma Research Laboratories, Pharmacia & Upjohn AB, Upssala, Sweden.
Tajallaei
S
S
Stjernschantz
J
J
D000284:Administration, Oral; D000287:Administration, Topical; D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D005123:Eye / Q000378:metabolism*; D005243:Feces / Q000737:chemistry; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D007275:Injections, Intravenous; D007429:Intraocular Pressure / Q000187:drug effects*; D000077338:Latanoprost; D008252:Macaca fascicularis; D008297:Male; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011461:Prostaglandins F, Synthetic / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D011355:Prodrugs; D011461:Prostaglandins F, Synthetic; D000077338:Latanoprost