The overall goals of this grant have been and continue to be the elucidation of the pharmacokinetics and pharmacodynamics of drugs affecting the kidney. Whereas previously the focus was jointly on diuretics and nonsteroidal anti-inflammatory drugs (NSAIDs), the current submission is solely for studies concerning the latter, accounting for a change in the title of the grant. Goals of the current application include: 1. Studies in man to assess the effect of short versus long duration of action NSAIDs on renal function in patients with mild to moderate renal insufficiency. Prior data from our laboratory indicated that short acting NSAIDs had no overall adverse effect on renal function because they allowed recovery of renal function within the dosing interval. Thus, long-acting NSAIDs could cause persistent decrements in renal function in susceptible patients. We wish to prospectively explore this issue, and link renal functional effects to the stereo-selective pharmacokinetics of ibuprofen (short-acting) and piroxicam (long-acting) or to a sustained release preparation of ibuprofen. 2. Studies to quantify in vivo in healthy man the pharmacokinetics of the enantiomers of ibuprofen and the chiral inversion of R- to S-ibuprofen. 3. To assess whether the S-enantiomer of arylpropionic NSAIDs is the active moiety in terms of renal PG inhibition, we will assess in healthy man the renal effects of R- compared to S-ketoprofen. Use of this compound will avoid the confounding effects of chiral inversion in interpreting the data. 4. Studies in patients with renal insufficiency to assess the potential clinical importance of a """"""""futile cycle"""""""" of elimination of arylpropionic NSAIDs via formation of acylglucuronide metabolites. To do so, we will use NSAIDs which do not undergo chiral inversion; namely, flurbiprofen and ketoprofen. 5. In vitro studies of the mechanisms of chiral inversion specifically addressing the relationship between in vivo inversion and the ability in vitro to form thioesters with acetyl CoA.
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