Differential inhibition of cyclooxygenases-1 and -2 by meloxicam and its 4′-isomer

Pairet, M.; Ryn, Joanne van; Schierok, H.; Mauz, A.; Trummlitz, Guenter; Engelhardt, G.

doi:10.1007/s000110050329

Cited by 91 publications

(53 citation statements)

References 23 publications

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“…Nevertheless, the sensitivity of MRP4 to some NSAIDs might affect blood tests used to determine the COX activity of newer NSAIDs. These tests often measure release of TxB 2 and PGE 2 from blood cells in which COX activity is stimulated (51). Our results suggest that such assays might be confounded by inhibition of prostanoid transport mechanisms, as seen in HEK293 cells expressing PGT.…”

Section: Discussionmentioning

confidence: 93%

The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs

Reid

Wielinga

Zelcer

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

471

371

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Prostaglandins are involved in a wide variety of physiological and pathophysiological processes, but the mechanism of prostaglandin release from cells is not completely understood. Although poorly membrane permeable, prostaglandins are believed to exit cells by passive diffusion. We have investigated the interaction between prostaglandins and members of the ATP-binding cassette (ABC) transporter ABCC [multidrug resistance protein (MRP)] family of membrane export pumps. In inside-out membrane vesicles derived from insect cells or HEK293 cells, MRP4 catalyzed the time-and ATP-dependent uptake of prostaglandin E 1 (PGE1) and PGE2. In contrast, MRP1, MRP2, MRP3, and MRP5 did not transport PGE 1 or PGE 2. The MRP4-mediated transport of PGE1 and PGE2 displayed saturation kinetics, with K m values of 2.1 and 3.4 M, respectively. Further studies showed that PGF 1␣, PGF2␣, PGA1, and thromboxane B 2 were high-affinity inhibitors (and therefore presumably substrates) of MRP4. Furthermore, several nonsteroidal antiinflammatory drugs were potent inhibitors of MRP4 at concentrations that did not inhibit MRP1. In cells expressing the prostaglandin transporter PGT, the steady-state accumulation of PGE 1 and PGE2 was reduced proportional to MRP4 expression. Inhibition of MRP4 by an MRP4-specific RNA interference construct or by indomethacin reversed this accumulation deficit. Together, these data suggest that MRP4 can release prostaglandins from cells, and that, in addition to inhibiting prostaglandin synthesis, some nonsteroidal antiinflammatory drugs might also act by inhibiting this release. P rostaglandins are key mediators in the regulation of many physiological processes. They are involved in inflammatory responses and tumorigenesis, and their synthesis and metabolism are tightly regulated (1). The first step in prostaglandin synthesis is the production of arachidonic acid, which is released from membrane lipid primarily by cytosolic phospholipase A 2 (1). Arachidonic acid is then oxidized to the intermediate prostaglandin H 2 (PGH 2 ) by PGH synthases, also known as cyclooxygenase (COX)-1 and -2, and the recently identified COX-3 (2). These enzymes are known clinically as the targets of aspirin and other nonsteroidal antiinf lammatory drugs (NSAIDs) (3). Moreover, several recent studies have shown a link between COX-2 expression and carcinogenesis. Prostaglandins are overproduced by a variety of tumors, leading to the suggested prophylactic use of COX-2 inhibitors to decrease the incidence of colon cancer (4, 5). After COX-mediated synthesis, PGH 2 is further converted by tissue-specific prostaglandin synthases into PGE 2 , PGF 2␣ , PGD 2 , prostacyclin, or thromboxane B 2 , the biologically active molecules (1).Prostaglandins are formed and secreted by most cells, and act as autocrine-or paracrine-signaling molecules. In many cases they exert their effects extracellularly via interaction with a family of G protein-coupled membrane receptors (reviewed in ref. 6), although some prostaglandins interact with the nuclear horm...

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Section: Discussionmentioning

confidence: 93%

The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs

Reid

Wielinga

Zelcer

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

471

371

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“…Meloxicam (MLX) is a non-steroidal antiinflammatory drug that is prescribed in the treatment of rheumatoid arthritis and osteoarthritis with low gastrointestinal complications (Pairet et al, 1998;Distel et al, 1996;Ahmed, Khanna, Furst, 2005;Aoki et al, 2006). MLX is practically insoluble in water (belonging to BCS Class II) and exhibits a slow oral absorption and slow onset of action (Budavari et al, 2001;Ghorab et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Preparation and physicochemical characterization of meloxicam orally fast disintegration tablet using its solid dispersion

Shoormeij

Taheri

Homayouni

2018

Braz. J. Pharm. Sci.

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Meloxicam (MLX) is a non-steroidal, anti-inflammatory drug that is prescribed in the treatment of rheumatoid arthritis and osteoarthritis. MLX is practically insoluble in water and exhibits a slow onset of action. In this study, MLX solid dispersions (MLX SDs) were prepared to improve the water solubility of this poorly water-soluble drug. Then orally disintegrating tablets (ODT) of MLX were developed using MLX SD to decrease the onset of action of this drug. MLX, poloxamer 188, and crospovidone of different ratios were melted in molten poloxamer 188 as a hydrophilic carrier. The optimum SD with the highest saturation solubility in water (13.09±0.34 microgram/mL) consisting of MLX: poloxamer 188: crospovidone in the ratio of 1:2:0 was used for the preparation of MLX ODTs. MLX ODTs were prepared by the direct compression method and optimized by the 2 3 factorial design. The effect of the superdisintegrant concentration, the mannitol-avicel ratio, and the level of compression force on the disintegration time, hardness, and percent of dissolved MLX from MLX ODTs after 30 min was evaluated. DSC and XRD analysis approved an amorphous form of MLX in SDs. The optimized ODT formulation containing 10% of superdisintegrant, and mannitol and avicel in the ratio of 4:1 respectively was compressed using a high level of compression force. The optimized ODT showed hardness (34.37±2.1 N) and friability (1.26±0.04%). This formulation showed a rapid disintegration in 12.66±2.5 seconds, which 82.66±5.1% of the MLX released within 30 min. MLX ODTs, prepared from MLX SD, could be introduced as a suitable dosage form of MLX with improved solubility and the onset of action.

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“…Indomethacin is a COX-1 preferential inhibitor (Barnett et al 1994;Blanco et al 1999). Meloxicam (Pairet et al 1998;Blanco et al 1999), SC58125 (Anderson et al 1996) and CAY10404 (Katada et al 2005) are defined as COX-2 inhibitors. Nordihydroguaiaretic acid (NDGA) was reported to be a selective LOX inhibitor (Mayer et al 1986).…”

Section: Histological Examinationmentioning

confidence: 99%

“…The concentration of each drug was decided based on the minimum concentration at which the drug inhibits PGE2 activity or pain. (Nakayama et al 1998;Pairet et al 1998;Katada et al 2005)…”

Section: Drug Administrationmentioning

confidence: 99%

The Non-steroidal Anti-inflammatory Drugs Protect Mouse Cochlea against Acoustic Injury

Hoshino

Tabuchi

Hirose

et al. 2008

Tohoku J. Exp. Med.

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Differential inhibition of cyclooxygenases-1 and -2 by meloxicam and its 4′-isomer

Cited by 91 publications

References 23 publications

The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs

The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs

Preparation and physicochemical characterization of meloxicam orally fast disintegration tablet using its solid dispersion

The Non-steroidal Anti-inflammatory Drugs Protect Mouse Cochlea against Acoustic Injury

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