Oxaprozin and Piroxicam, Nonsteroidal Antiinflammatory Drugs with Long Half‐Lives: Effect of Protein‐Binding Differences on Steady‐State Pharmacokinetics

Abstract

The nonsteroidal antiinflammatory drugs (NSAIDs) oxaprozin and piroxicam have long elimination half-lives (t 1/2 approximately 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, cross-over 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% (t1/2, 53.0 versus 57.4 hours; apparent oral clearance adjusted for 70-kg body weight [Clpo], 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 Clpo (Clpo,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 Clpo (Clpo,sd) values of both NSAIDs were significantly correlated in the study populations. With both NSAIDs, Clpo 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, Clpo,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.

Effect of gastric emptying and entero-hepatic circulation on bioequivalence assessment of ranitidine

“…According to previous studies, piroxicam, just like ranitidine, is known as a drug with EHC (27-31, 14, 32). Figures 2 and 3 however confirm that ranitidine does not have similar long elimination time in humans as stated for piroxicam (23,(32)(33)(34).…”

Hepatic Cytochrome P450 Abundance and Activity in the Developing and Adult Göttingen Minipig: Pivotal Data for PBPK Modeling

“…In human, CYP enzyme activity studies showed higher clearance in males for CYP1A2-(Caucasian population only) (Shimada et al, 1994) and CYP2E1-associated substrates (Sato et al, 1975;Chen et al, 2002;Franconi et al, 2007), whereas CYP3A4- (Austin et al, 1980;Kahan et al, 1986;Hulst et al, 1994;Dilger et al, 1999;Krecic-Shepard et al, 2000) and CYP2B6-associated (Lamba et al, 2003) clearance were higher in females for various substrates, although conflicting data have been reported and interindividual differences may prevail (Yang et al, 2013;Tracy et al, 2016). Conflicting results were also obtained for CYP2C9 (Houghton et al, 1975;Rugstad et al, 1986;Karim et al, 1997), CYP2C19 (Richardson et al, 1985;Rugstad et al, 1986;Hooper and Qing, 1990;Laine et al, 2000) and CYP2D6 (Walle et al, 1989;Pritchard et al, 1992;Tamminga et al, 1999;Labbé et al, 2000;Hägg et al, 2001;McCune et al, 2001;Aichhorn et al, 2007) depending on the substrate. Moreover, CYP2C19 and CYP2D6 are highly polymorphic genes, which makes it even more challenging to draw conclusions (Goldstein, 2001;Cascorbi, 2003).…”

Protein Binding of Piroxicam Studied by Means of Affinity Chromatography and Circular Dichroism

“…Piroxicam is included in the list of commonly used drugs that bind to site I on albumin (Srinivasan et al 1995); the extent of binding is 99Á3%. Karim et al (1997) investigated the effect of this binding behaviour on the disposition kinetics of piroxicam at steady state and it was shown that HSA binding was not dependent on plasma concentration.…”