Indomethacin - How It Works
Clinical pharmacology details from the US FDA-approved label: how Indomethacin works in your body, how it's absorbed, how long it stays active, and how it's eliminated.
Mechanism of Action
12.1 Mechanism of Action Indomethacin has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of indomethacin extended-release capsules, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Indomethacin is a potent inhibitor of prostaglandin synthesis in vitro . Indomethacin concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because indomethacin is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Indomethacin has analgesic, anti-inflammatory, and antipyretic properties.
The mechanism of action of indomethacin extended-release capsules, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).
Indomethacin is a potent inhibitor of prostaglandin synthesis in vitro .
Indomethacin concentrations reached during therapy have produced in vivo effects.
Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models.
Prostaglandins are mediators of inflammation.
Because indomethacin is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.
12.3 Pharmacokinetics Absorption Following single oral doses of indomethacin immediate-release capsules 25 mg or 50 mg, indomethacin is readily absorbed, attaining peak plasma concentrations of about 1 and 2 mcg/mL, respectively, at about 2 hours.
Orally administered indomethacin immediate- release capsules are virtually 100% bioavailable, with 90% of the dose absorbed within 4 hours.
A single 50 mg dose of indomethacin oral suspension was found to be bioequivalent to a 50 mg indomethacin Capsule when each was administered with food.
With a typical therapeutic regimen of 25 or 50 mg three times a day, the steady-state plasma concentrations of indomethacin are an average 1.4 times those following the first dose.
Indomethacin extended-release capsules 75 mg are designed to release 25 mg of the drug initially and the remaining 50 mg over approximately 12 hours (90% of dose absorbed by 12 hours).
When measured over a 24-hour period, the cumulative amount and time-course of indomethacin absorption from a single indomethacin extended-release capsule are comparable to those of 3 doses of 25 mg indomethacin immediate-release capsules given at 4 to 6 hour intervals Plasma concentrations of indomethacin fluctuate less and are more sustained following administration of indomethacin extended-release capsules than following administration of 25 mg indomethacin immediate-release capsules given at 4 to 6 hour intervals.
In multiple-dose comparisons, the mean daily steady-state plasma level of indomethacin attained with daily administration of indomethacin extended-release capsules 75 mg was indistinguishable from that following indomethacin immediate-release capsules 25 mg given at 0, 6 and 12 hours daily.
However, there was a significant difference in indomethacin plasma levels between the two dosage regimens especially after 12 hours.
Distribution Indomethacin is highly bound to protein in plasma (about 99%) over the expected range of therapeutic plasma concentrations.
Indomethacin has been found to cross the blood-brain barrier and the placenta, and appears in breast milk.
Elimination Metabolism Indomethacin exists in the plasma as the parent drug and its desmethyl, desbenzoyl, and desmethyldesbenzoyl metabolites, all in the unconjugated form.
Appreciable formation of glucuronide conjugates of each metabolite and of indomethacin are formed.
Excretion Indomethacin is eliminated via renal excretion, metabolism, and biliary excretion.
Pharmacokinetics
12.3 Pharmacokinetics Absorption Following single oral doses of indomethacin immediate-release capsules 25 mg or 50 mg, indomethacin is readily absorbed, attaining peak plasma concentrations of about 1 and 2 mcg/mL, respectively, at about 2 hours. Orally administered indomethacin immediate- release capsules are virtually 100% bioavailable, with 90% of the dose absorbed within 4 hours. A single 50 mg dose of indomethacin oral suspension was found to be bioequivalent to a 50 mg indomethacin Capsule when each was administered with food. With a typical therapeutic regimen of 25 or 50 mg three times a day, the steady-state plasma concentrations of indomethacin are an average 1.4 times those following the first dose. Indomethacin extended-release capsules 75 mg are designed to release 25 mg of the drug initially and the remaining 50 mg over approximately 12 hours (90% of dose absorbed by 12 hours). When measured over a 24-hour period, the cumulative amount and time-course of indomethacin absorption from a single indomethacin extended-release capsule are comparable to those of 3 doses of 25 mg indomethacin immediate-release capsules given at 4 to 6 hour intervals Plasma concentrations of indomethacin fluctuate less and are more sustained following administration of indomethacin extended-release capsules than following administration of 25 mg indomethacin immediate-release capsules given at 4 to 6 hour intervals. In multiple-dose comparisons, the mean daily steady-state plasma level