Inverse nonlinear pharmacokinetics of total and protein unbound drug (oxaprozin): clinical and pharmacokinetic implications.

The nonsteroidal antiinflammatory drug oxaprozin is extensively bound to plasma proteins in a concentration-dependent manner. This study demonstrates for the first time the inverse nonlinear pharmacokinetics of total and unbound oxaprozin and presents clinical implications of this phenomenon. A total of 71 healthy volunteers participated in single- and multiple-dose studies. In study I, 0.6-, 1.2-, and 1.8-gm doses of oxaprozin were given on an empty stomach in a randomized, crossover trial (n = 35). In studies II and III, 1.2- and 1.8-gm doses, respectively, were given once a day for 8 days (n = 12 and 24, respectively). Serial blood samples for total and unbound drug assays were taken over a 240-hour period in study I and for a 24-hour period on days 1, 5, and 8 in studies II and III. After administration of 1.2 gm once daily, steady-state conditions were established by day 5. Actual average steady-state plasma concentrations (Cavg) were lower than those predicted from the single-dose study based on linear kinetics for the total drug, but higher for the unbound drug. Nonlinear changes in Vd/F were also noted with multiple-dose administration. Vd/F increased by 47% for total drug but decreased by 61% for unbound drug relative to single-dose values. Half-lives after single-dose administration for total and unbound drug determined from 24 to 240 hours and from 24 to 72 hours, respectively, were dose independent for total drug, but dose dependent for unbound drug. Half-lives after multiple-dose administration measured from 24 to 48 hours in study II decreased further. In conclusion, oxaprozin clearance for the total drug was increased while that of the unbound drug was decreased after repetitive dosing. This inverse pharmacokinetic behavior has been attributed to the two noncompensatory kinetic effects: concentration-dependent protein binding and saturable metabolism of oxaprozin.