Differentiating among nonsteroidal antiinflammatory drugs by pharmacokinetic and pharmacodynamic profiles.
Cyclooxygenase (COX)-1 inhibition by nonsteroidal antiinflammatory drugs (NSAIDs) is associated with gastrointestinal and renal toxicity, while COX-2 inhibition has beneficial antiinflammatory, analgesic, and antipyretic effects. The measurement of inhibitory potency of NSAIDs on COX isoforms is strongly influenced by variations in experimental conditions in different models. The concentration of protein in the assay medium is particularly important because NSAIDs are highly protein-bound in vivo, and assays based on human whole blood provide the most suitable test system available. Of the drugs investigated in the human whole blood assay, only meloxicam showed selectivity for COX-2 at therapeutically relevant concentrations. In contrast, standard NSAIDs, such as naproxen, inhibited both COX isoforms to an equal degree at therapeutically relevant concentrations. Thus, the selectivity of NSAIDs against COX-2 relative to COX-1 may provide a means of differentiating between them according to their risk of toxicity at therapeutic doses. This may be more clinically meaningful than the traditional classification of NSAIDs based on chemical structure.
Fenner
H
H
Swiss Federal Institute of Technology, Zürich, Switzerland.
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000187:drug effects* / Q000378:metabolism; D000077239:Meloxicam; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects* / Q000378:metabolism; D013379:Substrate Specificity; D013843:Thiazines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013929:Thromboxane B2 / Q000096:biosynthesis
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D013843:Thiazines; D013844:Thiazoles; D013929:Thromboxane B2; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D000077239:Meloxicam