Comparison between isopropyl unoprostone and latanoprost by prostaglandin E(2)induction, affinity to prostaglandin transporter, and intraocular metabolism.
The pharmacological differences between isopropyl unoprostone (referred to as unoprostone) and latanoprost, concerning their induction of endogenous prostaglandin E(2)(PGE(2)) and affinity to a human prostaglandin transporter (PGT), were investigated. Freshly dissected bovine iris tissues were incubated with major intraocular metabolites of unoprostone, M1 and M2, acid of latanoprost, or PGF(2 alpha), and PGE(2)induction was measured. Affinities of M1, M2, latanoprost, acid of latanoprost, and PGF(2 alpha)to PGT molecule were measured using PGT-cDNA transfected HeLa cells by an isotopic influx assay.(3)H-unoprostone was incubated with freshly prepared serum, aqueous humor, or frozen stored fetal bovine serum (FBS), and the radioactivity of supernatants was measured to investigate their metabolism of(3)H-unoprostone.M2, acid of latanoprost, and PGF(2 alpha)significantly increased a release of PGE(2)compared with the control. 10 microM indomethacin completely inhibited PGE(2)induction by acid of latanoprost and PGF(2 alpha), while 100 microM indomethacin was required to inhibit PGE(2)induction completely by M1 and M2. Unoprostone, M1, M2, and latanoprost showed little affinity to PGT, while acid of latanoprost had an affinity to PGT. Freshly prepared serum and aqueous humor metabolized unoprostone, but frozen stored FBS did not. The release of endogenous PGE(2)may play an important role of action by means of PG analogs, and differences in indomethacin-related inhibition of PGE(2)release and in affinities to PGT may in part cause their different actions.
Kashiwagi
Kenji
K
Department of Ophthalmology, Yamanashi Medical University, Japan. kenjik@res.yamanashi-med.ac.jp
Kanai
Naoaki
N
Tsuchida
Takayuki
T
Suzuki
Michihiro
M
Iizuka
Yoko
Y
Tanaka
Yuko
Y
Tsukahara
Shigeo
S
D000328:Adult; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D017920:Antiporters / Q000378:metabolism*; D001082:Aqueous Humor / Q000378:metabolism; D002417:Cattle; D046508:Culture Techniques; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis*; D006367:HeLa Cells; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007498:Iris / Q000187:drug effects* / Q000378:metabolism; D000077338:Latanoprost; D027361:Organic Anion Transporters; D011461:Prostaglandins F, Synthetic / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D000959:Antihypertensive Agents; D017920:Antiporters; D016861:Cyclooxygenase Inhibitors; D004268:DNA-Binding Proteins; D027361:Organic Anion Transporters; D011461:Prostaglandins F, Synthetic; C503526:SLCO2A1 protein, human; C072630:isopropyl unoprostone; D000077338:Latanoprost; D015237:Dinoprost; D015232:Dinoprostone; D007213:Indomethacin