CLINICAL PHARMACOKINETICS OF TENOXICAM

Tenoxicam is a nonsteroidal anti-inflammatory drug (NSAID) in the oxic am group. It is completely absorbed by the oral route and is about 99% protein bound in human plasma. Intake of food delays absorption witho ut affecting bioavailability. There is no evidence for enterohepatic r ecycling 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 fas ted healthy volunteers 1.9 hours (1.0 to 5.0 hours) after a single ora l dose of 20mg. A mean elimination half-life of 67 hours (49 to 81 hou rs) has been estimated. Tenoxicam demonstrates linear single-dose phar macokinetics over doses of 10 to 100mg. Because of its low lipophilici ty and high degree of ionisation in blood (approximate to 99%), the dr ug is poorly distributed to body tissues and is slowly taken up by hep atic 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 o ral and intravenous administration. Peak concentrations of tenoxicam i n synovial fluid are less than one-third of those in plasma and they a ppear later, 20 hours (10 to 34 hours) after an oral dose. A parallel decrease in synovial fluid and plasma concentrations with time for bot h total and unbound tenoxicam has been reported. In vivo pH difference s between synovial fluid and plasma in patients with rheumatoid arthri tis 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 dif ferent groups of individuals, are not conclusive. The protein binding of tenoxicam is pH dependent. The drug is almost entirely eliminated b y liver metabolism. The 2 main metabolites, the inactive 5'-hydroxy an d 6-O-glucuronidated forms, are excreted in urine and bile, respective ly. The existence of additional metabolites in human bile has been sug gested. Urinary excretion of the 5'-hydroxy metabolite decreases with reduced renal function. The 5'-hydroxy metabolite is detected in plasm a in concentrations 1 to 5% of the parent compound and its decline par allels that of the parent compound (formation-rate limitation). Urinar y and faecal excretion of unchanged tenoxicam is less than 1% of the a dministered dose. No significant amounts of unchanged tenoxicam are ex creted in bile. Tenoxicam shows nearly linear pharmacokinetics during multiple-dose administration. The 6 to 18% underestimation of accumula tion when predicted from single-dose pharmacokinetic data is thought t o be of minor clinical significance. An equal degree of underestimatio n is found for all categories of individuals investigated, so tenoxica m steady-state concentrations are easily predicted. The long eliminati on half-life of the drug produces small and similar fluctuations in st eady-state concentrations both in plasma and synovial fluid, which sho uld justify single daily doses. Apart from a protein-binding displacem ent interaction with aspirin (acetylsalicylic acid), tenoxicam demonst rates a low interaction profile with most other drugs. However, high p lasma bilirubin concentrations (>100 to 200 mu mol/L) may predispose p atients to displacement of tenoxicam from plasma albumin binding sites .