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Oxaprozin and Piroxicam, Nonsteroidal Antiinflammatory Drugs with Long Half‐Lives: Effect of Protein‐Binding Differences on Steady‐State Pharmacokinetics
Author(s) -
Karim Aziz,
Noveck Robert,
McMahon F. Gilbert,
Smith Margo,
Crosby Sharon,
Adams Marijke,
Wilton John
Publication year - 1997
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/j.1552-4604.1997.tb04302.x
Subject(s) - piroxicam , pharmacokinetics , volume of distribution , pharmacology , steady state (chemistry) , crossover study , chemistry , oral administration , cyp2d6 , half life , medicine , cytochrome p450 , metabolism , alternative medicine , pathology , placebo
The nonsteroidal antiinflammatory drugs (NSAIDs) oxaprozin and piroxicam have long elimination half‐lives (t 1/2 ∼55 hours), permitting once‐daily dose regimens. The protein‐binding characteristics of these drugs, however, vary widely. This study examines the effect of these binding differences on the drugs' disposition kinetics at steady state. A total of 52 participants (26 young healthy volunteers and 26 elderly osteoarthritic patients, 15 men and 37 women (2 of them poor metabolizers of debrisoquine [ CYP2D6 ] ) completed the two‐period, two‐treatment, randomized, single‐dose and 21‐day, once‐daily multiple‐dose, crossover study. Doses of oxaprozin and piroxicam were 1,200 mg once daily and 20 mg once daily, respectively. Mean single‐dose kinetic parameters of oxaprozin versus piroxicam did not differ more than ±14% (t 1/2 , 53.0 versus 57.4 hours; apparent oral clearance adjusted for 70‐kg body weight [ Cl po ], 0.139 versus 0.121 L/hr; apparent volume of distribution adjusted for 70‐kg body weight [ Vd/F ], 10.2 L versus 9.13 L). Protein binding was plasma‐concentration dependent with oxaprozin (range, 10–400 mg/L) but not with piroxicam (range, 1–30 mg/L). Steady‐state conditions were established within 3 days with oxaprozin but took almost 12 days with piroxicam. Compared with the single‐dose values, steady‐state Cl po (Cl po, ss ) and Vd/F of total drug increased with oxaprozin by almost 127% but remained within ±10% with piroxicam. Post—steady‐state apparent t 1/2 of the total and unbound drugs of approximately 62 hours were similarly prolonged with piroxicam but differed substantially with oxaprozin (50.6 hours [ total drug ] versus 23.8 hours [ unbound drug ] ). Single dose Cl po (Cl po, sd ) values of both NSAIDs were significantly correlated in the study populations. With both NSAIDs, Cl po in the two poor metabolizers of debrisoquine was within ±20% of mean values for the population. Clinically important age‐ and gender‐dependent decreases were not observed in the weight‐adjusted, Cl po, sd or Vd/F values of the total drug for either NSAID. Clearances of the two NSAIDs were significantly correlated, suggesting that a common P450 isozyme (most likely CYP2C9, in that piroxicam is a known substrate of this isozyme) may be at least partly involved in the oxidative metabolism of these NSAIDs .