Partition behavior and ion pair formation of some prostaglandins.

Uekama, Kaneto; Hirayama, Fumitoshi; Tanaka, Harumi; Takematsu, Katsumi

doi:10.1248/cpb.26.3779

Cited by 20 publications

(3 citation statements)

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“…As charged organic anions at physiological pH (16,17), PGs traverse biological membranes poorly (18). Accordingly, PG transport is carrier-mediated in many diverse tissues, including the lung (19)(20)(21)(22), choroid plexus (23)(24)(25)(26)(27)(28), liver (29), anterior chamber of the eye (23)(24)(25)30), vagina and uterus (31)(32)(33), and placenta (34,35).…”

Section: Introductionmentioning

confidence: 99%

Cloning, in vitro expression, and tissue distribution of a human prostaglandin transporter cDNA(hPGT).

Lu¹,

Kanai²,

Bao³

et al. 1996

J. Clin. Invest.

209

138

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We recently identified a cDNA in the rat that encodes a broadly expressed PG transporter (PGT). Because PGs play diverse and important roles in human health and disease, we cloned human PGT (hPGT) from an adult human kidney cDNA library. A consensus sequence (4.0 kb) derived from several clones, plus 3 Ј polymerase chain reaction amplification, exhibited 74% nucleic acid identity and 82% amino acid identity compared to rat PGT. When transiently expressed in HeLa cells, a full-length clone catalyzed the transport of PGE 1 , PGE 2 , PGD 2 , PGF 2 ␣ and, to a lesser degree TXB 2 . Northern blotting revealed mRNA transcripts of many different sizes in adult human heart, placenta, brain, lung, liver, skeletal muscle, pancreas, kidney, spleen, prostate, ovary, small intestine, and colon. hPGT mRNAs are also strongly expressed in human fetal brain, lung, liver, and kidney. The broad tissue distribution and substrate profile of hPGT suggest a role in the transport and/or metabolic clearance of PGs in diverse human tissues. ( J. Clin. Invest.

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Section: Introductionmentioning

confidence: 99%

Cloning, in vitro expression, and tissue distribution of a human prostaglandin transporter cDNA(hPGT).

Lu¹,

Kanai²,

Bao³

et al. 1996

J. Clin. Invest.

209

138

View full text Add to dashboard Cite

show abstract

“…At physiologic pH, PGs predominate as the charged organic anion (9) and diffuse poorly through the lipid bilayer (10,11). Facilitated, carrier-mediated PG transport has been demonstrated by many diverse tissues including the lung (8,12), liver (13), kidney (14), vagina and uterus (15), and blood-brain and blood-intraocular fluid barriers (16).…”

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confidence: 99%

Mechanism of Prostaglandin E2 Transport across the Plasma Membrane of HeLa Cells and Xenopus Oocytes Expressing the Prostaglandin Transporter “PGT”

Chan¹,

Satriano²,

Pucci³

et al. 1998

Journal of Biological Chemistry

127

101

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We recently identified a novel prostaglandin transporter called PGT (Kanai, N., Lu, R., Satriano, J. A., Bao, Y., Wolkoff, A. W., and Schuster, V. L. (1995) Science 268, 866 -869). Based on initial functional studies, we have hypothesized that PGT might mediate the release of newly synthesized prostaglandins (PG), epithelial transport of PGs, or metabolic clearance of PGs. Here we examined the mechanism of PGT transport as expressed in HeLa cells and Xenopus oocytes, using isotopic PG influx and efflux studies. In both native HeLa cells and oocytes, cell membranes were poorly permeable to PGs. In contrast, in oocytes injected with PGT mRNA, the PG influx permeability coefficient was 90 -157 times that of oocytes injected with water. The rank order substrate profile was PGF 2␣ Ϸ PGE 2 > TXB 2 > > 6 keto-PGF 1␣ . PG influx displayed an overshoot with rapid accumulation of tracer PGE 2 , followed by a gradual return to baseline. Based on estimated oocyte volumes, the PGT-mediated accumulation of PGE 2 reached steady state at intraoocyte concentrations 25-fold higher than the external media. The accumulation of PG was not due to intracellular binding or metabolism. PGT-mediated uptake was ATP-and temperature-dependent, but not sodium-dependent, and was inhibited by disulfonic stilbenes, niflumic acid, and the thiol reactive anion MTSES (Na(2-sulfonatoethyl)methanethiosulfonate). Prostaglandins (PGs)1 and thromboxanes have broad physiologic and pathophysiologic effects, regulating cellular processes in nearly every tissue. They elicit potent actions on the cardiovascular, gastrointestinal, respiratory and reproductive systems, and are important mediators of inflammation, fever, and pain (2). As autacoids, PGs are synthesized by intracellular enzymes at or near their sites of action before they are presented to adjacent PG receptors. Thereafter, extracellular PGs are metabolized in situ within seconds before they are able to reach the general circulation (3, 4). At least in the case of PGE 2 and PGF 2␣ , loss of biologic activity is due to cellular uptake followed by intracellular oxidation (5-8).At physiologic pH, PGs predominate as the charged organic anion (9) and diffuse poorly through the lipid bilayer (10, 11). Facilitated, carrier-mediated PG transport has been demonstrated by many diverse tissues including the lung (8, 12), liver (13), kidney (14), vagina and uterus (15), and blood-brain and blood-intraocular fluid barriers (16).The clearance and metabolism of PGs from the pulmonary circulation has been widely studied using the isolated, perfused rat lung model where concentrative uptake of PGs has been described followed by the appearance of metabolites in the venous effluent (8,17). Substances that inhibit PG transport reduce PG inactivation by the lung (18). Moreover, whereas PGE 1 , PGF 2␣ , PGD 2 , and PGI 2 are all good substrates for the oxidizing enzyme 15-hydroxyprostaglandin dehydrogenase, PGI 2 escapes pulmonary metabolism (8). These phenomena are best explained by selective, carrier-mediated PG tr...

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“…Cyclodextrins form inclusion complexes with various drug molecules (4-8). Since I is essentially a methyl ester of long chain unsaturated fatty acids, the relatively hydrophobic cyclodextrin cavity is expected to attract I as an adequate guest molecule (9)(10)(11). Thus, the present study dealt with inclusion complexation of I with ( Y -and 0-cyclodextrins in anticipation of improved solubilization and stabilization of I.…”

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confidence: 99%

Improvements of Dissolution Characteristics and Chemical Stability of 16,16-Dimethyl-trans-Δ2-prostaglandin E1 Methyl Ester by Cyclodextrin Complexation

Uekama

Hirayama

Yamada

et al. 1979

Journal of Pharmaceutical Sciences

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Partition behavior and ion pair formation of some prostaglandins.

Cited by 20 publications

References 0 publications

Cloning, in vitro expression, and tissue distribution of a human prostaglandin transporter cDNA(hPGT).

Cloning, in vitro expression, and tissue distribution of a human prostaglandin transporter cDNA(hPGT).

Mechanism of Prostaglandin E2 Transport across the Plasma Membrane of HeLa Cells and Xenopus Oocytes Expressing the Prostaglandin Transporter “PGT”

Improvements of Dissolution Characteristics and Chemical Stability of 16,16-Dimethyl-trans-Δ2-prostaglandin E1 Methyl Ester by Cyclodextrin Complexation

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