Etodolac - How It Works
Clinical pharmacology details from the US FDA-approved label: how Etodolac works in your body, how it's absorbed, how long it stays active, and how it's eliminated.
CLINICAL PHARMACOLOGY Pharmacodynamics Etodolac is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models.
The mechanism of action of etodolac, like that of other NSAIDs, is not completely understood, but may be related to the prostaglandin synthetase inhibition.
Etodolac is a racemic mixture of [-]R- and [+]S-etodolac.
As with other NSAIDs, it has been demonstrated in animals that the [+]S-form is biologically active.
Both enantiomers are stable and there is no [-]R to [+]S conversion in vivo.
Pharmacokinetics Absorption The systemic bioavailability of etodolac from etodolac tablet is 100% as compared to solution and at least 80% as determined from mass balance studies.
Etodolac is well absorbed and had a relative bioavailability of 100% when 200 mg capsules were compared with a solution of etodolac.
Based on mass balance studies, the systemic availability of etodolac from the tablet formulation is at least 80%.
Etodolac does not undergo significant first-pass metabolism following oral administration.
Mean (± 1 SD) peak plasma concentrations (C max ) range from approximately 14 ± 4 to 37 ± 9 mcg/mL after 200 to 600 mg single doses and are reached in 80 ± 30 minutes (see Table 1 for summary of pharmacokinetic parameters).
The dose-proportionality based on the area under the plasma concentration-time curve (AUC) is linear following doses up to 600 mg every 12 hours.
Peak concentrations are dose proportional for both total and free etodolac following doses up to 400 mg every 12 hours, but following a 600 mg dose, the peak is about 20% higher than predicted on the basis of lower doses.
The extent of absorption of etodolac is not affected when etodolac tablets are administered after a meal.
Food intake, however, reduces the peak concentration reached by approximately one-half and increases the time to peak concentration by 1.4 to 3.8 hours.
Mean (CV%) * Pharmacokinetic Parameters of Etodolac in Normal Healthy Adults and Various Special Populations PK Parameters Normal Healthy Adults (18 to 65) † Healthy Males (18 to 65) Healthy Females (27 to 65) Elderly (>65) (70 to 84) Hemodialysis (24 to 65) (n=9) Renal Impairment (46 to 73) Hepatic Impairment (34 to 60) (n=179) (n=176) (n=3) Dialysis On Dialysis Off (n=10) (n=9) T max , h 1.4 (61%) * 1.4 (60%) 1.7 (60%) 1.2 (43%) 1.7 (88%) 0.9 (67%) 2.1 (46%) 1.1 (15%) Oral Clearance, mL/h/kg (CL/F) 49.1 (33%) 49.4 (33%) 35.7 (28%) 45.7 (27%) NA NA 58.3 (19%) 42 (43%) Apparent Volume of Distribution, mL/kg (Vd/F) 393 (29%) 394 (29%) 300 (8%) 414 (38%) NA NA NA NA Terminal Half-Life, h 6.4 (22%) 6.4 (22%) 7.9 (35%) 6.5 (24%) 5.1 (22%) 7.5 (34%) NA 5.7 (24%) NA = not available * % Coefficient of variation † Age Range (years) Distribution The mean apparent volume of distribution (Vd/F) of etodolac is approximately 390 mL/kg.
Etodolac is more than 99% bound to plasma proteins, primarily to albumin.
The free fraction is less than 1% and is independent of etodolac total concentration over the dose range studied.
It is not known whether etodolac is excreted in human milk; however, based on its physical-chemical properties, excretion into breast milk is expected.
Data from in vitro studies, using peak serum concentrations at reported therapeutic doses in humans, show that the etodolac free fraction is not significantly altered by acetaminophen, ibuprofen, indomethacin, naproxen, piroxicam, chlorpropamide, glipizide, glyburide, phenytoin, and probenecid.
Metabolism Etodolac is extensively metabolized in the liver.
Pharmacokinetics
Pharmacokinetics Absorption The systemic bioavailability of etodolac from etodolac tablet is 100% as compared to solution and at least 80% as determined from mass balance studies. Etodolac is well absorbed and had a relative bioavailability of 100% when 200 mg capsules were compared with a solution of etodolac. Based on mass balance studies, the systemic availability of etodolac from the tablet formulation is at least 80%. Etodolac does not undergo significant first-pass metabolism following oral administration. Mean (± 1 SD) peak plasma concentrations (C max ) range from approximately 14 ± 4 to 37 ± 9 mcg/mL after 200 to 600 mg single doses and are reached in 80 ± 30 minutes (see Table 1 for summary of pharmacokinetic parameters). The dose-proportionality based on the area under the plasma concentration-time curve (AUC) is linear following doses up to 600 mg every 12 hours. Peak concentrations are dose proportional for both total and free etodolac following doses up to 400 mg every 12 hours, but following a 600 mg dose, the peak is about 20% higher than predicted on the basis of lower doses. The extent of absorption of etodolac is not affected when etodolac tablets are administered after a meal. Food intake, however, reduces the peak concentration reached by approximately one-half and increases the time to peak concentration by 1.4 to 3.8 hours. Table 1. Mean (CV%) * Pharmacokinetic Parameters of Etodolac in Normal Healthy Adults and Various Special Populations PK Parameters