Purchase this article with an account.
U. C. Welge-Lussen, M. Kraft, D. Auge, U. Schlötzer-Schrehardt, M. F. Fromm, F. Kruse, O. Zolk; The Uptake Transporter Oatp2a1 Might Be Involved in the Intraocular Disposition of Prostanoids. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4060.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
The mechanisms of ocular uptake and distribution of locally applied prostanoids for glaucoma treatment are not well understood. We hypothesized that Organic anion transporting polypeptides (OATPs) are responsible for uptake of topically applied prostanoids into ocular tissues.
Concentrations of latanoprost in aqueous humour samples obtained from 12 patients 91±43 min after topical application were determined by Liquid Chromatography/Mass Spectrometry/Mass Spectrometry (LC/MS/MS). Transcript levels of the uptake transporters OATP2A1 and OATP2B1 were determined in human ocular tissues (ciliary body, choroidea, retina, iris, lens, and cornea, n=2) by real-time RT-PCR. The inhibitory interactions of therapeutically used prostanoid (tafluprost, bimatoprost, latanoprost, travoprost) and their therapeutically active metabolites (the respective free acid) with the uptake of prototypical substrates were tested in stably transfected HEK cells overexpressing either OATP2A1 or OATP2B1.
We observed remarkable interindividual variations in latanoprost levels (mean15±14 ng/ml, minimum 1 ng/ml, maximum 44 ng/ml, coefficient of variation 87%), supporting the idea that transporters might be involved in the intraocular disposition of prostanoids. Expression of all transporters was highest in the ciliary body and choroidea, and was much lower in human retina, iris, lens, and cornea. OATP2A1 and MRP4 mRNA levels in the ciliary body and choroidea were markedly higher (4.0 to 6.3-fold) than in human liver whereas OATP2B1 mRNA expression was more than 15-fold lower in eye tissues than in liver. IC-50 values for inhibition of bromosulfophthalein uptake by OATP2B1 varied from 10-23 µM (travoprost, latanoprost) to 312 µM (tafluprost). IC-50 values for inhibition of prostaglandin E2 uptake by OATP2A1 ranged from 0.7-0.9 µM (latanoprost, bimatoprost free acid) to 90 µM (tafluprost). Uptake experiments revealed that the acid of latanoprost was a transported substrate of OATP2A1 (K-m 3.6 µM, V-max 83.5 pmol/mg protein/min), but was not transported by OATP2B1.
This PDF is available to Subscribers Only