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Metabolism and kinetics of oxaprozin in normal subjects
Author(s) -
Janssen Frank W,
Jusko William J,
Chiang Soong T,
Kirkman Sandra K,
Southgate Peter J,
Coleman Anthony J,
Ruelius Hans W
Publication year - 1980
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.1980.47
Subject(s) - glucuronidation , chemistry , biotransformation , pharmacokinetics , metabolite , hydroxylation , volume of distribution , urine , metabolism , distribution volume , kinetics , absorption (acoustics) , oral administration , pharmacology , distribution (mathematics) , drug , glucuronic acid , excretion , biochemistry , microsome , enzyme , medicine , polysaccharide , mathematical analysis , physics , mathematics , quantum mechanics , acoustics
Absorption, biotransformation, excretion, and kinetics of Oxaprozin (4,5‐diphenyl‐2‐oxazolepropionic acid) were examined in subjects after an oral dose of 14 C‐Oxaprozin alone as well as before, during, and after long‐term administration of unlabeled drug. A single dose of 14 C‐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 glucuronidatum 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 l4 C‐Oxaprozin. Following a single dose, the kinetic parameters for 14 C and unchanged drug in plasma were nearly the same. A 2‐compartment model with first‐order elimination adequately describes kinetic disposition. The slow clearance (Cl p ), 0.08 to 0.12 l/hr, was almost entirely due to biotransformation and the plasma half‐lifes, which ranged from 49 to 69 hr, reflected the small Cl p . The small volume of distribution (V Dβ = 8 to 9 l) indicates limited extravascular distribution. Multiple doses of unlabeled drug, especially when given concurrently, increased the Cl p of 14 C‐oxaprozin. This effect is apparently related to decreased binding of high concentrations of Oxaprozin to plasma protein. As a result of increased Cl p , steady‐state levels are only 40% of levels predicted from the single‐dose study. Clinical Pharmacology and Therapeutics (1980) 27, 352–362; doi: 10.1038/clpt.1980.47