The overall goals of this proposal are to address issues (particularly in elderly patients) concerning the clinical toxicology of drugs that represent one of the most frequently prescribed group of agents. Literally millions of patients each day take the drugs we propose to study. New data, largely generated from our laboratory, have identified unique metabolic pathways, namely chiral inversion and futile cycling, that may have important toxicological ramifications. The general aim of this proposal is to better understand the mechanisms of these pathways, to quantify them in relevant patient groups and to explore their biologic/toxicologic relevance. Through our prior grant support, this laboratory has pursued questions concerning the pharmacokinetics and pharmacodynamics of nonsteroidal anti- inflammatory drugs (NSAIDs). As a logical sequel to prior studies in this area, we propose addressing the following questions relevant to arylpropionic NSAIDs: 1) Does administration of pure S(+)-ibuprofen avoid formation of hybrid triglycerides and phospholipids as occurs with administration of the antipode? In turn, does administration of pure S-ibuprofen avoid persistence of ibuprofen in plasma as occurs with dosing of the racemate? 2) Does formation of hybrid triglycerides result in a decreased ability to hydrolyze the ibuprofen from the glycerol backbone? Does the same apply to hydrolysis by phospholipase A2 of hybrid phospholipids? 3) Does formation of coenzyme A thioesters from ibuprofen result in incorporation of ibuprofen into cell membranes? 4) Does futile cycling of ketoprofen coupled with its chiral inversion result in accumulation of the active S-enantiomer in elderly patients? In turn, does accumulation result in adverse renal effects?
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