title: Pharmacokinetic and pharmacodynamic aspects of the ideal COX-2 inhibitor: a pharmacologist's perspective.
abstract: Two classes of antipyretic analgesics were developed about 100 years ago, namely the acidic aspirin-like drugs and non-acidic acetaminophen-phenazone-like compounds. Since then, research has aimed at improving the side-effect profile of the acidic anti-inflammatory aspirin-like drugs and improving the anti-inflammatory efficacy of the non-acidic acetaminophen-phenazone-like compounds. Both drug classes inhibit the cyclooxygenase (COX)-1 and -2 enzymes non-selectively. The aspirin-like drugs achieve particularly high concentrations in inflamed tissue, which is assumed to account for their superior anti-inflammatory potency. These acidic drugs also reach comparatively high concentrations in the stomach wall, kidney cortex and blood, resulting in the well-known side effects that occur with acidic compounds but not with acetaminophen and phenazone. Following the discovery of the two differentially distributed and regulated COXs, two non-acidic COX-2-selective compounds--celecoxib and rofecoxib--were introduced. They proved to be less toxic to the gastrointestinal tract compared with, for example, diclofenac or naproxen. These non-acidic drugs distribute homogeneously throughout the body--a cause for concern since COX-2 has been found to be present constitutively in many organ systems, including brain, bone and the genito-urinary tract. It appears desirable to combine the tissue-targeted distribution of the highly protein-bound acidic aspirin-type drugs with the selectivity of the COX-2 inhibitors, in order to achieve improved anti-inflammatory activity and at the same time reduce the risk of side effects. Such agents should be devoid of COX-1-related side effects in, for example, the inhibition of blood coagulation and should only weakly affect COX-2 related functions of the central nervous system, due to slow blood-brain barrier penetration. We therefore propose that a drug combining the pharmacokinetic characteristics of, for example, ibuprofen with the COX-2 selectivity of rofecoxib is likely to be a superior anti-inflammatory analgesic.
authors.affiliation: Institute for Pharmacology and Toxicology, University of Erlangen, Fahrstrasse 17, 91054 Erlangen, Germany. Kay.Brune@pharmakologie.uni-erlangen.de
authors.forename: K
authors.initials: K
authors.lastname: Brune
authors.forename: A
authors.initials: A
authors.lastname: Neubert
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000493:pharmacokinetics; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D006801:Humans; D007052:Ibuprofen / Q000493:pharmacokinetics; D007527:Isoenzymes / Q000378:metabolism*; D007783:Lactones / Q000493:pharmacokinetics; D008565:Membrane Proteins; D010600:Pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D013379:Substrate Specificity; D013450:Sulfones
chemical_list: D018712:Analgesics, Non-Narcotic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D007783:Lactones; D008565:Membrane Proteins; D013450:Sulfones; C116926:rofecoxib; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D007052:Ibuprofen