s25ab_9

Pharmacokinetic and pharmacodynamic aspects of the ideal COX-2 inhibitor: a pharmacologist's perspective

K. Brune, A. Neubert

Institute for Pharmacology and Toxicology, Universität Erlangen, Erlangen, Germany

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 Ð celecoxib and rofecoxib Ð 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 Ð 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.

Key words: NSAIDs, rofecoxib, celecoxib, pharmacokinetics, pharmacodynamics, half-life, synovial fluid, clearance, absorption.

Please address correspondence and reprint requests to: Professor Dr. Kay Brune, Institute for Pharmacology and Toxicology, University of Erlangen, Fahrstrasse 17, 91054 Erlangen, Germany.
E-mail: Kay.Brune@pharmakologie.uni-erlangen.de