Single- and multiple-dose pharmacokinetics, kidney tolerability and plasma protein binding of tenoxicam in renally impaired patients and healthy volunteers.
The 20 mg single-dose and 12 days repeated-dose pharmacokinetics of tenoxicam and the 5-OH-tenoxicam metabolite have been evaluated in healthy volunteers and two groups of patients with different degree of renal impairment, in total 20 persons. Concomitantly, the plasma protein binding of tenoxicam and the effects of treatment on renal function were evaluated. No differences were found between the investigated groups in the pharmacokinetics of total tenoxicam and the 5-OH metabolite did not interfere either with the pharmacokinetics or with the plasma protein binding of tenoxicam. A positive correlation was found between an increase in the free fraction (% F) of tenoxicam in plasma and a decrease in the plasma elimination half-life in the low creatinine clearance group (40-20 ml/min.) both after the single-dose and at steady-state. At steady-state, a non-linear correlation was demonstrated between a decrease in the urinary excretion of the 5-OH metabolite and a decrease in creatinine clearance from 130 to 20 ml/min. An increase in the plasma level of the 5-OH metabolite by three times was found in the low creatinine clearance group as compared to healthy subjects. 14C-Impurities of tenoxicam, as low as 1.2%, were shown to greatly influence the determination of the plasma protein binding (equilibrium dialysis) of the highly protein-bound tenoxicam due to a non-binding ability of the impurities to plasma proteins. No significant changes in renal parameters were found during the study. It can be concluded that the pharmacokinetics and plasma protein binding of tenoxicam and the pharmacokinetics of the 5-OH-tenoxicam metabolite are increasingly changed in subjects with a creatinine clearance below 40 ml/min. A decreased binding of tenoxicam to plasma proteins in low clearance patients is probably the reason for a faster elimination of tenoxicam in this group rather than a higher intrinsic hepatic metabolic activity. This study conducted in a low number of patients did not bring forward any new data indicating any adverse effects of tenoxicam on renal function.
Nilsen
O G
OG
Department of Environmental Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim. Odd.Nilsen@medisin.ntnu.no
Aasarød
K
K
Widerøe
T E
TE
Guentert
T W
TW
D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism / Q000493:pharmacokinetics*; D001798:Blood Proteins / Q000378:metabolism*; D003404:Creatinine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D007674:Kidney Diseases / Q000378:metabolism*; D007677:Kidney Function Tests; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010894:Piroxicam / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics*; D011485:Protein Binding / Q000187:drug effects; D013997:Time Factors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001798:Blood Proteins; D010894:Piroxicam; D003404:Creatinine; C032801:tenoxicam