Absorption, biotransformation, excretion, and kinetics of oxaprozin (4,5-diphenyl-2-oxazolepropionic acid) were examined in subjects after an oral dose of 14C-oxaprozin alone as well as before, during, and after long-term administration of unlabeled drug. A single dose of 14C-oxaprozin was rapidly absorbed and the unchanged drug was essentially the only labeled substance in plasma. Recovery of radioactivity in excreta, mostly in urine, exceeded 90%. Major biotransformation routes were glucuronidation of the carboxyl group and hydroxylation of the phenyl rings followed by glucuronidation. Administration of unlabeled oxaprozin did not affect the absorption, qualitative, or quantitative metabolite profile, or recovery of 14C-oxaprozin. Following a single dose, the kinetic parameters for 14C and unchanged drug in plasma were nearly the same. A2-compartment model with first-order elimination adequately describes kinetic disposition. The slow clearance (Clp), 0.08 to 0.12 1/hr, was almost entirely due to biotransformation and the plasma half-lifes, which ranged from 49 to 69 hr, reflected the small Clp. The small volume of distribution (VD beta = 8 to 9 1) indicates limited extravascular distribution. Multiple doses of unlabeled drug, especially when given concurrently, increased the Clp of 14C-oxaprozin. This effect is apparently related to decreased binding of high concentrations of oxaprozin to plasma protein. As a result of increased Clp, steady-state levels are only 40% of levels predicted from the single-dose study.