Etodolac:

Absorption:

Etodolac is well absorbed and has a systemic availability of at least 80%. It does not undergo significant first-pass metabolism following oral administration. Mean (± 1 SD) peak plasma concentrations (Cmax) range from approximately 14 ± 4 to 37 ± 9 µg/mL after single dose and are reached in 80 ± 30 minutes. The dose-proportionality based on the area under the plasma concentration-time curve (AUC) is linear every 12 hours. The extent of absorption of etodolac is not affected when 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.

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 it is excreted in human milk; however, based on its physical-chemical properties, excretion into breast milk is expected.

Metabolism:

Etodolac is extensively metabolized in the liver. Several etodolac metabolites have been identified in human plasma and urine. After a single dose, hydroxylated metabolites accounted for less than 10% of total drug in serum. On chronic dosing, hydroxylated-etodolac metabolite does not accumulate in the plasma of patients with normal renal function. The hydroxylated-etodolac metabolites undergo further glucuronidation followed by renal excretion and partial elimination in the feces.

Excretion:

The mean oral clearance of etodolac following oral dosing is 49 (± 16) mL/h/kg. Approximately 1% dose is excreted unchanged in the urine with 72% of the dose excreted into urine as parent drug plus metabolite. Fecal excretion accounted for 16% of the dose.

Paracetamol:

Absorption:

Paracetamol is well absorbed in the gastrointestinal tract. Oral bioavailability is dose dependant: with larger doses, the hepatic first pass effect is reduced due to overwhelming of the liver enzymatic capacity; and therefore, bioavailability is increased. Rectal administration of paracetamol is also feasible. In this case, bioavailability is inconsistent and in overall reduced, due to incomplete dissolution of the suppository in the rectum. The absorption rate through this route of administration is elongated.

Distribution:

Paracetamol is distributed throughout the body fluids in a homogeneous way. The analgesic activity is attributable to the small fraction that penetrates into the brain. Paracetamol given at therapeutic doses binds to plasma proteins at less than 20%. In case of intoxication, this proportion may increase to up to 50%.

Metabolism:

Paracetamol is essentially metabolized in the liver by conjugation with glucuronic acid (55%) and sulfuric acid (35%). Hepatotoxic metabolites are produced in small amounts by the cytochrome P450 (isoenzyme CYP2E1). In the therapeutic plasma concentration range, this metabolite is detoxified by conjugation with glutathione.

Elimination:

Metabolites are excreted through the kidneys in the urine. Only 2-5% of the dose is excreted in an unchanged form in the urine. As a consequence of its short elimination half-life (1-3h), 24 hours after the ingestion of a single dose of paracetamol, 98% of the dose is eliminated.