Clinical Pharmacokinetics of Tenoxicam

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Abstract

Summary

Tenoxicam is a nonsteroidal anti-inflammatory drug (NSAID) in the oxicam group. It is completely absorbed by the oral route and is about 99% protein bound in human plasma. Intake of food delays absorption without affecting bioavailability. There is no evidence for enterohepatic recycling of the drug in humans. Peak plasma concentrations of 2.7 mg/L (range 2.3 to 3.0 mg/L) have been reported in different groups of fasted healthy volunteers 1.9 hours (1.0 to 5.0 hours) after a single oral dose of 20mg. A mean elimination half-life of 67 hours (49 to 81 hours) has been estimated. Tenoxicam demonstrates linear single-dose pharmacokinetics over doses of 10 to 100mg. Because of its low lipophilicity and high degree of ionisation in blood (≈99%), the drug is poorly distributed to body tissues and is slowly taken up by hepatic cells. A small apparent volume of distribution of 9.6L (7.5 to 11.5L), and low total plasma clearance of 0.106 L/h (0.079 to 0.142 L/h), have been reported in different groups of healthy volunteers after oral and intravenous administration.

Peak concentrations of tenoxicam in synovial fluid are less than one-third of those in plasma and they appear later, 20 hours (10 to 34 hours) after an oral dose. A parallel decrease in synovial fluid and plasma concentrations with time for both total and unbound tenoxicam has been reported. In vivo pH differences between synovial fluid and plasma in patients with rheumatoid arthritis may indicate significantly lower concentrations of unbound ionised tenoxicam in synovial fluid than in plasma. Data on relative binding capacities for tenoxicam in plasma and synovial fluid, and between different groups of individuals, are not conclusive. The protein binding of tenoxicam is pH dependent.

The drug is almost entirely eliminated by liver metabolism. The 2 main metabolites, the inactive 5′-hydroxy and 6-O-glucuronidated forms, are excreted in urine and bile, respectively. The existence of additional metabolites in human bile has been suggested. Urinary excretion of the 5′-hydroxy metabolite decreases with reduced renal function. The 5′-hydroxy metabolite is detected in plasma in concentrations 1 to 5% of the parent compound and its decline parallels that of the parent compound (formation-rate limitation). Urinary and faecal excretion of unchanged tenoxicam is less than 1% of the administered dose. No significant amounts of unchanged tenoxicam are excreted in bile.

Tenoxicam shows nearly linear pharmacokinetics during multiple-dose administration. The 6 to 18% underestimation of accumulation when predicted from single-dose pharmacokinetic data is thought to be of minor clinical significance. An equal degree of underestimation is found for all categories of individuals investigated, so tenoxicam steady-state concentrations are easily predicted. The long elimination half-life of the drug produces small and similar fluctuations in steady-state concentrations both in plasma and synovial fluid, which should justify single daily doses.

Apart from a protein-binding displacement interaction with aspirin (acetylsalicylic acid), tenoxicam demonstrates a low interaction profile with most other drugs. However, high plasma bilirubin concentrations (>100 to 200 μmol/L) may predispose patients to displacement of tenoxicam from plasma albumin binding sites.

No significant differences have been demonstrated in either single- or multiple-dose pharmacokinetics of tenoxicam in healthy volunteers, patients with rheumatic or inflammatory diseases, renal failure, liver cirrhosis (single-dose studies only) or in the elderly. Thus, no dosage adjustments seem justified for these patients on the basis of pharmacokinetics. However, some attention should be paid to long term treatment of patients with liver disease, especially those patients with elevated plasma bilirubin.

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