Additional materials
Determination of lumiracoxib and etoricoxib
Concentrations of lumiracoxib and etoricoxib were measured by means of validated LC-MS/MS assays in human plasma and microdialysate. 10 µL Aliquots (1) were measured by means of validated LC-MS/MS assays in human plasma and microdialysate. Aliquots (10 µL)of the samples were spiked with 10 µL of a solution containing the internal standard (IS), desmethylcelecoxib in acetonitrile (5000 ng/mL). Then,After adding 10 µL acetonitrilewere added to simulate the addition of the standard and 400 µL water:acetonitrile (20:80, v/v). After this,), the samples were vortexed for 1 minute, centrifuged at 15,000 rpm (17,000 g) and transferred to the HPLC vials in preparation for injection. Sample analysis was performed usingSamples were analyzed by means ofliquid chromatography–electrospray ionization-tandem mass spectrometry (LC–ESI-MS/MS). The LC equipment consisted of an Agilent 1100 Series binary pump (G1312A) and degasser (G1379A) (Waldbronn, Germany) connected to an HTC PAL autosampler (Chromtech, Idstein, Germany). A triple quadrupole mass spectrometer 4000 QTRAP, equipped with a Turbo V IonSpray SourceIonSpraySource was used for detection (ABSciex, Darmstadt, Germany). High purity nitrogen for the mass spectrometer was produced by the nitrogen generator NGM 22-LC/MS (cmc Instruments, Eschborn, Germany). Chromatographic separations were obtained in the isocratic mode using a Synergi MAX-RP column (150 × 2mm I.D., 4 μm particle size and 80 Å pore size) (Phenomenex, Aschaffenburg, Germany). The mobile phase consisted of water: acetonitrile 15:85, v/v. 10 μL AliquotsμLAliquotsof the extracted samples for the determination of lumiracoxib and 5 µL for etoricoxib were injected into the LC-ESI-MS/MS. The temperature of the sample compartment of the auto-sampler was set at 6 °C. The flow rate was set at 0.3mL/min. The mass spectrometer was operated in the positive ion mode for etoricoxib and negative ion mode for lumiracoxib. Precursor-to-product ion transitions of m/z 292.0 → 248.2 for lumiracoxib (collision energy -18 V), m/z 366.0 → 302.1 for the IS (32 V) and m/z 358.9 → 279.9 for etoricoxib (45 V) were used to quantify the multiple reaction monitoring (MRM). All quadrupoles were working at unit resolution. Integration was performed with Analyst Software V1.5 (AB SciexABSciex, Darmstadt, Germany). A calibration curve, from 5 to 50,000 ng/mL for lumiracoxib and from 1 to1to 20,000 ng /mL for etoricoxib, was prepared by spiking 10 µL of the appropriate acetonitrile working solutions in the corresponding matrix. The lower limits of quantification (LLOQ) were 5 ng/mL for lumiracoxib and 1 ng/mL for etoricoxib. Variations in accuracy and intra-day and inter-day precision were < 15 % over the range of calibration.
Analysis of arachidonic acid metabolites
The content of PGE2, PGD2 , PGF2and 6and6-keto-PGF1in unstimulated and LPS-stimulated blood andbloodand dialysate was determined by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) (25). )(2).Prostaglandins were separated with a Synergi Hydro-RP column (150 x 2mm I.D., 4 µm particle size and 80 Å pore size from Phenomenex, Aschaffenburg, Germany) and determined in an API 4000 triple quadrupole mass spectrometer (AB SciexABSciex, Darmstadt, Germany).
Standard and plasma sample preparation
Samples for standard curve and quality control were prepared with 250 µL PBS, 100 µL 0.15M EDTA, 600 µL 45 mM45mM H3PO4, 10 µL BHT (2 mg/mL in methanol), 20 µL working standards and 20 µL internal standards solution ([2H4]-PGE2, [2H4]-PGD2, [2H4]-PGF210 ng10ng/mL and [2H4]-6-keto-PGF125 ng25ng/mL, all in methanol). Plasma samples were prepared similarly: instead of 250 µL PBS and 20 µL working standard, 250 µL humanµLhuman plasma and 20 µL methanoland20 µLmethanol were used. Prostaglandins were extracted by solid-phase-extraction. Briefly, 1mL Chromabond HR-X cartridges (Macherey-Nagel, Düren, Germany) were washed with 2 mL of hexane/ethyl acetate/isopropanol (35:60:5, v/v), dried for 20 s, conditioned with 1 mL of methanol and equilibrated with 1 mL of water. A 1 mL aliquot of plasma sample/standard was loaded into the column and washed with 1 mL of water and 1 mL of methanol/water (20:80, v/v). The cartridges were then dried for 7 minutes and eluted with 1 mL of hexane/ethyl acetate/isopropanol (35:60:5,v/v). The organic phase was removed at a temperature of 45 °C under a gentle stream of nitrogen. The residues were reconstituted with 50 µL of acetonitrile/water/formic acid (20:80:0.0025, v/v, pH 4.0), centrifuged for 2 minutes at 10,000 g and then transferred to glass vials (Macherey-Nagel, Düren, Germany) prior to injection into the LC-MS/MS system. TheLLOQ was 10pg/mL for each analyte.
Standard and microdialysissample preparation
Samples for the standard curve and quality controls were prepared with 40 µL PBS, 100 µL 0.15 M EDTA, 600 µL ethyl acetate, 20 µL working standards and 20 µL internal standards solution ([2H4]-PGE2, [2H4]-PGD2, [2H4]-PGF2 10 ng/mL and [2H4]-6-keto-PGF1 25 ng/mL, all in methanol). Microdialysis samples were prepared similarly. However, instead of 40 µL PBS and 20 µL working standard, 40µL sample and 20 µL methanol were added. PGE2, PGD2, PGF26-keto-PGF1and internal standards were extracted twice using liquid-liquid-extraction. The organic phases were removed at a temperature of 45 °C under a gentle stream of nitrogen. The residues were reconstituted with 50 µL of acetonitrile/water/formic acid (20:80:0.0025, v/v, pH 4.0), centrifuged for 2 min at 10,000 g and then transferred to glass vials (Macherey-Nagel, Düren, Germany) prior to injection into the LC-MS/MS system.
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Detailed statistical results
Additional table 1: Whole blood concentrations of metabolites of arachidonic acid (AA).
AA metabolite / Drug / Time [h] / Unstimulated / LPS stimulated / rm-ANOVA Effects (significant effects italic)Mean [ng/mL] / Standard deviation / Mean [ng/mL] / Standard deviation / “Stimulation” / “Time” / “Medication” / “Time* stimulation” / “Time* medication” / “Medication * stimulation” / “Time* stimulation* medication”
PGE2 / Lumiracoxib / 24 / 0.08 / 0.09 / 12.1 / 8.1 / df = 1,16, F = 48.06, p = 0.000003 / df = 1,16, F = 13.35, p = 0.001 / df = 2,32, F = 18.51, p = 0.000005 / df = 1,16, F = 18.78, p = 0.001 / df = 2,32, F = 17.09, p = 0.000009 / df = 2,32, F = 17.95, p = 0.000006 / df = 2,32, F = 16. 46, p = 0.000011
26 / 0.07 / 0.14 / 2.9 / 3.0
Etoricoxib / 24 / 0.12 / 0.22 / 6.9 / 4.5
26 / 0.10 / 0.16 / 2.6 / 2.3
Placebo / 24 / 0.13 / 0.26 / 11.1 / 8.4
26 / 0.17 / 0.27 / 12.2 / 7.1
6-Keto-PGF1α / Lumiracoxib / 24 / BDL / BDL / BDL / BDL / - / - / - / - / - / - / -
26 / BDL / BDL / BDL / BDL
Etoricoxib / 24 / BDL / BDL / BDL / BDL
26 / BDL / BDL / BDL / BDL
Placebo / 24 / BDL / BDL / BDL / BDL
26 / BDL / BDL / BDL / BDL
PGD2 / Lumiracoxib / 24 / 0.68 / 2.71 / 0.43 / 1.53 / df = 1,16, F = 3.87, p = 0.067 / df = 1,16, F = 0.89, p = 0.36 / df = 2,32, F = 1.05, p = 0.362 / df = 1,16, F = 0.99, p = 0.334 / df = 2,32, F = 1.23, p = 0.306 / df = 2,32, F = 0.944, p = 0.399 / df = 2,32, F = 0.92, p = 0.409
26 / 0.34 / 1.37 / 0.94 / 3.74
Etoricoxib / 24 / 0.05 / 0.11 / 0.04 / 0.04
26 / 0.02 / 0.02 / 0.02 / 0.02
Placebo / 24 / 0.49 / 1.97 / 0.50 / 1.79
26 / 0.59 / 2.36 / 0.65 / 2.28
PGF2α / Lumiracoxib / 24 / 0.78 / 1.70 / 5.58 / 8.12 / df = 1,16, F = 5.84, p = 0.028 / df = 1,16, F = 0.35, p = 0.563 / df = 2,32, F = 0.567, p = 0.573 / df = 1,16, F = 0.436, p = 0.518 / df = 2,32, F = 1.45, p = 0.249 / df = 2,32, F = 0.551, p = 0.582 / df = 2,32, F = 1.416, p = 0.258
26 / 0.80 / 1.99 / 3.51 / 6.34
Etoricoxib / 24 / 0.39 / 0.75 / 4.50 / 5.98
26 / 0.35 / 0.46 / 3.98 / 6.43
Placebo / 24 / 1.34 / 4.13 / 4.54 / 8.94
26 / 0.55 / 1.21 / 13.32 / 43.50
BDL: Below detection limit.
Additional table 2: Concentrations of arachidonic acid (AA) metabolites in the dialysate, taken during the sampling periods -4 – 0 h before administration of the second dose of the medication (“Pre”), and 0 - +4 h after drug administration (“Post”).
AA metabolite / Drug / Time (relative to 2nd dose) / Control side / Freeze lesion side / rm-ANOVA Effects (significant effects italic)Mean [ng/mL] / Standard deviation / Mean [ng/mL] / Standard deviation / “Side” / “Time” / “Medication” / “Time* side” / “Time* medication” / “Medication * side” / “Time* side * medication”
PGE2 / Lumiracoxib / Pre / 0.117 / 0.227 / 0.11 / 0.134 / df = 1,16, F = 1.8, p = 0.198 / df = 1,16, F = 2.96, p = 0.105 / df = 2,32, F = 0.88, p = 0.426 / df = 1,16, F = 0.99, p = 0.334 / df = 2,32, F = 2.14, p = 0.163 / df = 2,32, F = 0.88, p = 0.426 / df = 2,32, F = 1.14, p = 0.333
Post / 0.03 / 0.069 / 0.076 / 0.13
Etoricoxib / Pre / 0.581 / 1.841 / 0.158 / 0.348
Post / 0.059 / 0.242 / 0.01 / 0.042
Placebo / Pre / 0.323 / 0.461 / 0.143 / 0.254
Post / 0.347 / 0.63 / 0.113 / 0.264
6-Keto-PGF1α / Lumiracoxib / Pre / 0.088 / 0.245 / 0.04 / 0.09 / df = 1,16, F = 0.52, p = 0.479 / df = 1,16, F = 2.72, p = 0.118 / df = 2,32, F = 0.23, p = 0.797 / df = 1,16, F = 0.89, p = 0.36 / df = 1,16, F = 2.98, p = 0.065 / df = 2,32, F = 1.28, p = 0.293 / df = 2,32, F = 0.007, p = 0.993
Post / 0.091 / 0.16 / 0.09 / 0.298
Etoricoxib / Pre / 0.078 / 0.238 / 0.066 / 0.21
Post / 0.068 / 0.23 / 0.093 / 0.267
Placebo / Pre / 0.016 / 0.049 / 0.038 / 0.116
Post / 0.049 / 0.116 / 0.11 / 0.216
PGD2 / Lumiracoxib / Pre / 0.147 / 0.247 / 0.207 / 0.637 / df = 1,16, F = 0.65, p = 0.430 / df = 1,16, F = 0.022, p = 0.885 / df = 2,32, F = 1.57, p = 0.224 / df = 1,16, F = 0.74, p = 0.402 / df = 2,32, F = 5.76, p = 0.007 / df = 2,32, F = 0.7, p = 0.506 / df = 2,32, F = 0.314, p = 0.733
Post / 0.127 / 0.197 / 0.221 / 0.43
Etoricoxib / Pre / 0.216 / 0.333 / 0.11 / 0.181
Post / 0.034 / 0.069 / 0.041 / 0.093
Placebo / Pre / 0.121 / 0.18 / 0.193 / 0.217
Post / 0.273 / 0.382 / 0.337 / 0.62
PGF2α / Lumiracoxib / Pre / 0.105 / 0.188 / 0.066 / 0.113 / df = 1,16, F = 0.026, p = 0.873 / df = 1,16, F = 8.14, p = 0.012 / df = 2,32, F = 1.7, p = 0.199 / df = 1,16, F = 5.9, p = 0.027 / df = 2,32, F = 0.48, p = 0.621 / df = 2,32, F = 0.56, p = 0.577 / df = 2,32, F = 0.634, p = 0.537
Post / 0.053 / 0.133 / 0.083 / 0.143
Etoricoxib / Pre / 0.145 / 0.217 / 0.12 / 0.17
Post / 0.058 / 0.097 / 0.127 / 0.212
Placebo / Pre / 0.142 / 0.186 / 0.12 / 0.192
Post / 0.096 / 0.139 / 0.092 / 0.148