title: The prostaglandin transporter OATP2A1 is expressed in human ocular tissues and transports the antiglaucoma prostanoid latanoprost.
abstract: OBJECTIVE
  Latanoprost, a prostaglandin F(2alpha) analogue, has become one of the most widely used medications for the treatment of glaucoma. The authors hypothesized that organic anion transporting polypeptides (OATPs) are responsible for the uptake of latanoprost into ocular tissues and, hence, that they contribute to the interindividual differences in drug concentrations and effects.
  
  
  METHODS
  Expression of prostaglandin (PG) transporters (OATP2A1, OATP2B1) in human ocular tissues was determined using real-time RT-PCR and immunofluorescence. The inhibitory interactions between latanoprost and its active metabolite (the free acid) and the uptake of prototypical substrates (PGE(2) and bromosulfophthalein) were tested in stably transfected human embryonic kidney cells overexpressing either OATP2A1 or OATP2B1. These cells were also used to investigate whether latanoprost and latanoprost acid are substrates of OATP2A1 or OATP2B1.
  
  
  RESULTS
  OATP2A1 and OATP2B1 mRNA expression was highest in the choroid/retinal pigment epithelium (RPE) complex and ciliary body. OATP2A1 protein expression was most prominent in the RPE and in epithelial and endothelial cell layers of anterior segment tissues, such as cornea, conjunctiva, iris, and ciliary body, whereas OATP2B1 protein was additionally expressed in trabecular meshwork, Schlemm canal, and choroidal vasculature. Latanoprost and latanoprost acid significantly inhibited both OATP2A1 and OATP2B1. Uptake experiments demonstrated that latanoprost acid is effectively transported by OATP2A1 (affinity constant [K(m)], 5.4 microM; maximum uptake rate [V(max)], 21.5 pmol/mg protein/min) and less effectively by OATP2B1.
  
  
  CONCLUSIONS
  The results presented herein suggest that at least OATP2A1 plays a role in the intraocular disposition of the therapeutically used prostanoid latanoprost.
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Michaela E
authors.initials: ME
authors.lastname: Kraft
authors.forename: Hartmut
authors.initials: H
authors.lastname: Glaeser
authors.forename: Kathrin
authors.initials: K
authors.lastname: Mandery
authors.forename: Jörg
authors.initials: J
authors.lastname: König
authors.forename: Daniel
authors.initials: D
authors.lastname: Auge
authors.forename: Martin F
authors.initials: MF
authors.lastname: Fromm
authors.forename: Ursula
authors.initials: U
authors.lastname: Schlötzer-Schrehardt
authors.forename: Ulrich
authors.initials: U
authors.lastname: Welge-Lüssen
authors.forename: Friedrich E
authors.initials: FE
authors.lastname: Kruse
authors.forename: Oliver
authors.initials: O
authors.lastname: Zolk
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000869:Anterior Eye Segment / Q000378:metabolism*; D000959:Antihypertensive Agents / Q000378:metabolism*; D001692:Biological Transport; D002460:Cell Line; D002829:Choroid / Q000378:metabolism*; D002853:Chromatography, Liquid; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D005786:Gene Expression Regulation / Q000502:physiology*; D005901:Glaucoma / Q000188:drug therapy; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects; D007668:Kidney / Q000196:embryology / Q000378:metabolism; D000077338:Latanoprost; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics* / Q000378:metabolism; D011461:Prostaglandins F, Synthetic / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053719:Tandem Mass Spectrometry; D014162:Transfection
chemical_list: D000959:Antihypertensive Agents; D027361:Organic Anion Transporters; D011461:Prostaglandins F, Synthetic; D012333:RNA, Messenger; C503526:SLCO2A1 protein, human; C450859:SLCO2B1 protein, human; D000077338:Latanoprost