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Indometacin

Analgesic
Proprietary names. Amuno; Artracin; Confortid; Flexin Continus; Imbrilon; Indochron;
Indocid; Indocin; Indoflex; Indolar; Indomax; Indotard; Maximet SR; Mobilan; Pardelprin;
Rheumacin; Rimacid; Slo-Indo.
1-(4-Chlorobenzoyl)-5methoxy2methyl1H-indole3acetic acid
C19H16ClNO4=357.8
CAS53861

A white to yellowtan, crystalline powder. M.p. about 155 to 162. It exhibits


polymorphism.
Practically insoluble in water; soluble 1 in 50 of ethanol, 1 in 30 of chloroform, and 1 in
about 40 of ether; soluble in acetone.

Dissociation Constant.
pKa4.5.

Partition Coefficient.
Log P(octanol/pH 7.4), 1.0.

Colour Tests.
Liebermann's Testblack; Mandelin's Testgrey; Marquis Testorange; Sulfuric Acid
orange

Thinlayer Chromatography.
System TARf 94; system TDRf 16; system TERf 05; system TFRf 13; system TG
Rf 20; system TADRf 38; system TAERf 83; system TAFRf 63; system TAJRf
46; system TAKRf 90; system TALRf 90. (Chromic acid solution, greybrown; acidified
potassium permanganate solution, positive.)

Gas Chromatography.

System GAindometacin RI 2550 (capillary), RI 2685 (packed); system GDRRTs of


methyl derivative 1.55 and 0.49 (relative to n-C16H34); system GLindometacin-Me RI 2770,
M (OH-)-Me2 RI 2880.

High Performance Liquid Chromatography.


System HDk 6.95; system HVRRT 0.87 (relative to meclofenamic acid); system HX
RI 607; system HYRI 590; system HZretention time 14.4 min; system HAAretention
time 21.7 min; system HAXretention time 8.5 min; system HAYretention time 9.2 min.

Ultraviolet Spectrum.
Methanolic acid318 nm (A11=180a); aqueous alkali230, 279 nm (A11=213a). (See below)

Infrared Spectrum.
Principal peaks at wavenumbers 1681, 1228, 1218, 1706, 1299, 1065 cm1 (KBr disk).

Mass Spectrum.
Principal ions at m/z 139, 141, 357, 111, 359, 140, 113, 75; M (OH-)-Me2 239, 298, 135, 191,
107, 103.

Quantification
Gas chromatography.
In plasma or urine: indometacin and desmethylindometacin, limit of detection 10 g/L, ECD
P. Guissou et al.,J. Chromatogr.,1983, 277(28) B Biomed. Appl., 368373.
Gas chromatographymass spectrometry.
In plasma or synovial fluid, limit of detection <0.1 g/LM. Dawson et al.,Biomed.
Environ. Mass Spectrom.,1990, 19, 453458. In plasma or urine: indometacin and other
NSAIDsA. K. Singh et al.,J. Chromatogr.,1991, 568, 351361.
High performance liquid chromatography.

In plasma or urine: indometacin and desmethylindometacin, limit of detection 25 g/L for


indometacin in plasma, fluorescence detectionM. S. Bernstein and M. A. Evans,J.
Chromatogr.,1982, 229(18) B Biomed. Appl., 179187. In serum: limit of detection 20 g/L
I. Roberts and I. M. Smith,Ann. Clin. Biochem.,1987, 24, 167171. In plasma: limit of
detection 10 g/L, spectrophotometric detectionP. Hubert et al.,J. Pharm. Biomed.
Anal.,1989, 7, 18191827. In plasma or urine: indometacin and other NSAIDs, limits of
detection 50 to 500 g/L, diodearray, UV, and fluorescence detectionA. K. Singh et al.,J.
Chromatogr.,1991, 568, 351361. In plasma: limit of detection <50 g/LA. G. Johnson and
J. E. Ray,Ther. Drug Monit.,1992, 14, 6165. In plasma or urine: indometacin and its
metabolites, limit of detection for indometacin <60 g/LT. B. Vree et al.,J.
Chromatogr.,1993, 616, 271282. In plasma: indometacin and mefanamic acid, limit of
detection for indometacin 60 g/L, UV detectionI. Niopas and K. Mamzoridi,J.
Chromatogr.,1994, 656 B Biomed. Appl., 447450. In plasma: limit of detection about
50 g/L, UV detectionJ. Sato et al.,J. Chromatogr. B. Biomed. Sci. Appl.,1997, 692, 241
244.
High performance liquid chromatographymass spectrometry.
In plasmaP. J. Taylor et al.,Ther. Drug Monit.,1998, 20, 691696.
Thinlayer chromatography.
In plasma or urine: limit of detection 30 g/LI. Soendergaard and E. Steiness,J.
Chromatogr.,1979, 162(4) B Biomed. Appl., 485488.
Radioimmunoassay.
In plasma or urine: limit of detection 50 g/LL. E. Hare et al.,J. Pharm. Sci.,1977, 66,
486489.

Disposition in the Body.


Readily and almost completely absorbed after oral administration. Indometacin is subject to
considerable enterohepatic circulation. Metabolic reactions include O-demethylation, Ndeacetylation, and glucuronic acid conjugation, the major metabolites being
desmethylindometacin (DMI), deschlorobenzoylindometacin (DBI), and
desmethyldeschlorobenzoylindometacin (DMBI) and their glucuronides. These substances,
together with unchanged indometacin and its glucuronide, are excreted in both the urine (up
to about 60% of the dose in 48 h) and the faeces (up to about 30% of the dose in 96 h) in
variable amounts. Expressed as a percentage of the dose, the average amounts excreted in the
urine in 48 h are: unchanged indometacin 5 to 20% (dependent on urinary pH), indometacin
glucuronide 6 to 26%, DMI and its glucuronide 8 to 23%, DBI and its glucuronide 4 to 20%,
DMBI and its glucuronide less than 3%; in the faeces the major metabolites found are DMBI
(up to about 16%) and DMI (up to about 12%), with only small amounts of unchanged
indometacin and DBI.
Therapeutic concentration.
In plasma, usually in the range 0.5 to 3 mg/L.

After a single oral dose of 50 mg given to 20 subjects, peak plasma concentrations of 1.0 to
3.0 mg/L (mean 1.9) were attained in 1 to 4. [K. C. Kwan et al.,J. Pharmacokinet.
Biopharm.,1976, 4, 255280.]
Steadystate plasma concentrations of 0.31 to 0.63 mg/L (mean 0.49) were attained in about
6 days after oral doses of 25 mg three times a day to 5 subjects. [G. Alvn et al.,Clin.
Pharmaol. Ther.,1975, 18, 364373.]
Toxicity.
Toxic effects may be produced by plasma concentrations greater than 5 mg/L.
Halflife.
Plasma halflife, 3 to 15 h.
Volume of distribution.
About 1 L/kg.
Clearance.
Plasma clearance, 1 to 2 mL/min/kg.
Distribution in blood.
Plasma:whole blood ratio, 1.9.
Protein binding.
In plasma, 90 to 99%.
Note.
For a review of the pharmacokinetics of indometacin see L. Helleberg,Clin.
Pharmacokinet.,1981, 6, 245258.

Dose.
50 to 200 mg daily.