Plasma and cerebrospinal fluid concentrations of indomethacin in children after intravenous administration.

The objective of this study was to evaluate the cerebrospinal fluid (CSF) permeation of indomethacin in healthy children. The participants (n = 31, aged 4-144 months) received indomethacin (0.35 mg/kg) as a 10-minute intravenous infusion prior to surgery under spinal anaesthesia. A single CSF and plasma sample from each individual was collected 14 to 225 minutes after the infusion. Indomethacin concentrations were determined from the CSF, plasma, and protein-free plasma. Total plasma, protein-free plasma, and CSF concentrations of indomethacin ranged between 90 and 2200 ng/mL (median, 780 ng/mL), 0.3 and 0.8 ng/mL (median, 0.5 ng/mL), and 0.2 and 5.0 ng/mL (median, 1.4 ng/mL), respectively. The CSF to plasma concentration ratio remained less than 0.01. There was no correlation between the administration time and CSF concentrations. Eleven children developed 12 nonserious adverse effects, from which 5 were central nervous system (CNS) effects (agitation). In conclusion, indomethacin permeated into the CSF of children, which enables both desired and adverse CNS effects of indomethacin.

Influence of plasma protein on the potencies of inhibitors of cyclooxygenase-1 and -2.

It is widely believed that the potencies of nonsteroid anti-inflammatory drugs (NSAIDs) as inhibitors of cyclooxygenase (COX) are influenced by protein binding in the extracellular fluid, since NSAIDs are bound to circulating albumin by well over 95%. This is an important point because the protein concentrations in synovial fluid and the central nervous system, which are sites of NSAID action, are markedly different from those in plasma. Here we have used a modified whole-blood assay to compare the potencies of aspirin, celecoxib, diclofenac, indomethacin, lumiracoxib, meloxicam, naproxen, rofecoxib, sodium salicylate, and SC560 as inhibitors of COX-1 and COX-2 in the presence of differing concentrations of protein. The potencies of diclofenac, naproxen, rofecoxib, and salicylate, but not aspirin, celecoxib, indomethacin, lumiracoxib, meloxicam, or SC560, against COX-1 (human platelets) increased as protein concentrations were reduced. Varying protein concentrations did not affect the potencies of any of the drugs against COX-2, with the exception of sodium salicylate (A549 cells). Clearly, our findings show that the selectivity of inhibitors for COX-1 and COX-2, which are taken to be linked to their efficacy and side effects, may change in different extracellular fluid conditions. In particular, selectivity in one body compartment does not demonstrate selectivity in another. Thus, whole-body safety or toxicity cannot be linked to one definitive measure of COX selectivity.

Protein binding of indomethacin in human cerebrospinal fluid.

The binding of the non-steroidal anti-inflammatory drug indomethacin to proteins in human cerebrospinal fluid (CSF), drawn during lumbar puncture from 10 patients affected by lumbosciatica, was measured by equilibrium dialysis and spectrofluorimetry. Similar binding studies on human serum albumin solutions (0.5 and 1 g/L) were performed using the same techniques. The mean binding percentage of indomethacin determined by equilibrium dialysis was 40%. The results obtained by both techniques allowed us to conclude that the binding of indomethacin in CSF was essentially due to albumin.

Plasma and cerebrospinal fluid concentrations of indomethacin in humans. Relationship to analgesic activity.

Plasma and cerebrospinal fluid (CSF) concentrations of indomethacin have been determined in 52 patients hospitalized for nerve-root compression pain. Samples of blood and CSF were collected at the same time in each subject, 0.5 to 12 h after a single intramuscular injection of 50 mg indomethacin. Analgesic effect was assessed by the absolute and percentage variation in Huskisson's visual analogue scale between dosing and sampling. According to its high lipid solubility, indomethacin rapidly crossed the blood-brain barrier, being detected in CSF 0.5 h after administration. After attainment of equilibrium within 2 h, the CSF level exceeded the free plasma level. Since the drug was extensively bound to serum albumin (99.7 +/- 0.1%), this phenomenon may represent a slight degree of binding of indomethacin in CSF. The analgesic activity was not related to either the plasma or CSF concentration of indomethacin.

Antipyretic mechanism of indomethacin in rabbits.

The mechanism of the antipyretic effect of indomethacin (IM) on fever induced by bacterial pyrogen (LPS, 0.2 microgram/kg, i.v.), leukocytic pyrogen (LP, 2 ml/kg, i.v.) and 2,4-dinitrophenol (DNP, 20 mg/kg, i.m.) in male adult rabbits was studied. In plasma, the biological half lives of IM in normal and LPS-injected rabbits were estimated to be 24 and 21 min in the early phase and 72 and 51 min in the late phase, respectively. A potent antipyretic effect was observed with intravenous injection of IM in LPS- and LP-induced fevers, but not in DNP-induced fever. The antipyretic effect was also observed with intracisternal injection of indomethacin at doses of 0.025 and 0.013 mg/kg. The activity of endogenous pyrogen in serum after LPS injection was not suppressed by the injection of IM (10 mg/kg, i.v.). The production of LP by leukocytes in vitro was not inhibited by IM (10 micrograms/ml). In our previous report, it was ascertained that the rectal temperature of normal rabbits remained unchanged after intravenous injection of IM. These results suggest that indomethacin may inhibit only the pyretic processes in the central nervous system.

Pharmacokinetics of indomethacin i.m. in blood, synovial fluid, synovial membrane, muscle, fat, bone, and spinal fluid.

Nonsteroidal anti-inflammatory drugs are an important part of the therapy of rheumatoid arthritis. For optimal dosage it would be necessary to know the levels of such compounds in inflamed tissue and not only in blood because the drugs inhibit prostaglandin synthesis in all cells of the body. In the present study, the levels of indomethacin in blood, synovial fluid, synovial membrane, muscle, fat, bone and spinal fluid of patients with rheumatoid arthritis have been measured at 1, 3, 6, and 12 hours after administration of 50 mg indomethacin (Amuno, Merck Sharp & Dohme). At 3, 6, 9 and 12 hours after administration levels in synovial fluid and tissue were higher than in blood but the differences were not significant. Levels in the other tissues investigated did not differ much from blood. In experiments with carrageenan-induced inflammation in rabbits, levels of indomethacin in blood and exudate have been measured after administration of 7.5 mg/kg i.v. Between 3 and 8 hours after administration levels in exudate were significantly higher than in blood. From the time course of indomethacin in blood compared to synovial fluid or exudate and from the comparison of the elimination half lives it can be concluded, that the transport of indomethacin into the inflamed area is mainly a process of diffusion.