Clinical Pharmacokinetics of Indomethacin

Abstract

Indomethacin (1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid) is an anit-in-flammatory antipyretic drug commonly used for symptomatic relief of pain and stiffness in rheumatic diseases. Following oral administration the absorption of the drug is rapid and complete, but with important inter-and intraindividual variations. In general, peak plasma concentrations of 2 to 3 microgram/ml are achieved with 1 to 2 hours, but concomitant ingestion of food reduces and delays the peak concentrations without reducing the amount absorbed. Rectal administration is associated with earlier but lower peak plasma concentrations, incomplete absorption form suppositories, and offers no clinical advantages when compared with equivalent oral dosage. In plasma at 90% of indomethacin is bound to albumin at therapeutic plasma concentrations. Indomethacin is distributed into the synovial fluid, is excreted in human breast milk and crosses the placenta in significant amounts. It is metabolised to O-desmethylindomethacin, N-deschlorobenzoylindomethacin and O-desmethy-N-deschlorobenzoylindomethacin, which are devoid of anti-inflammatory activity and are present in significant amount in the plasma. About 60% of an oral dose is excreted in the urine predominantly in glucuronidated form, while about 40% is excreted in the faeces after biliary secretion. A large amount of the dose undergoes biliary recycling. The biotransformation is independent of the route of administration. A 2-compartment open model with correction for biliary recycling can be used to describe the disposition of indomethacin. The drug has a biological half-life of about 5 to 10 hours and a plasma clearance of 1 to 2.5ml/kg/min. In premature infants the half-life of indomethacin is inversely correlated with gestational age and is significantly prolonged as compared with adults. Renal failure does not affect the serum concentrations of indomethacin. Probenecid results in increased plasma concentrations of indomethacin with enhanced pain relief without increasing the incidence of side effects. There seem to be no significant pharmacokinetic interactions between indomethacin and aspirin or warfarin. To date it has not been possible to identify a relationship between the clinical effects and plasma concentration of indomethacin.

Metabolism and Disposition of Indomethacin in Preterm Infants

“…Only 14% deacylated indomethacin based on the appearance of p-chlorobenzoic The predominance of déméthylation in these preterm infants contrasts to the pre dominance of deacylation in adult humans and some animal species [8]. However, de acylation occurs with doses higher than those given to preterm human infants whereas indomethacin in low concentrations is mainly demethylated [9], We found that indomethacin déméthyl ation is associated with shorter ti/" smaller AUC and higher Cl, p < 0.05. We confirm that failures of indomethacin-mediated sPDA closure are associated with lower peak plasma concentrations, c(0), larger Vd and faster plasma Cl, p< 0.01, p <0.005, p <0.01, respectively.…”

Enhancement of Doxorubicin Cytotoxicity on Human Esophageal Squamous Cell Carcinoma Cells by Indomethacin and 4-[5-(4-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (SC236) via Inhibiting P-Glycoprotein Activity

“…It is noteworthy that both indomethacin and SC236 are most likely to function as noncompetitive inhibitors for P-gp, which manifested by the inhibition of P-gp ATPase activity. The minimal effective concentration (2.5 M) of indomethacin used in the present experiments is almost three times lower than that in the plasma of the patients treated with indomethacin in the clinical trial (Helleberg, 1981). With respect to SC236, it has been reported that SC236 at the plasma concentration of 5 g/ml (12.5 M), which is five times higher than the minimal effective concentration (2.5 M) in our study, was used in an orthotopic xenograft mouse model (Lee et al, 2006).…”

Biotransformation of indomethacin by the fungus Cunninghamella blakesleeana1

“…It is extensively used because of its excellent pharmaceutical properties. Indomethacin is used in the treatment of musculoskeletal disorders such as rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and also as an adjunct to periodontal therapy [1][2][3] .…”