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

Two classes of antipyretic analgesics were developed about 100 years ago, n amely 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 t he anti-inflammatory efficacy of the non-acidic acetaminophen-phenazone-lik e compounds. Both drug classes inhibit the cyclooxygenase (COX) -1 and -2 e nzymes non-selectively. The aspirin-like drugs achieve particularly high co ncentrations in inflamed tissue, which is assumed to account for their supe rior anti-inflammatory potency. These acidic drugs also reach comparatively high concentrations in the stomach wall, kidney cortex and blood, resultin g in the well-known side effects that occur with acidic compounds but not w ith acetaminophen and phenazone. Following the discovery of the two differentially distributed and regulated COXs, two non-acidic COX-2-selective compounds - celecoxib and rofecoxib w ere 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 CO X-2 has been found to be present constitutively in many organ systems, incl uding brain, bone and the genito-urinary tract. It appears desirable to combine the tissue-targeted distribution of the hig hly 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. Stich agents should be de void 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 c entral nervous system, due to slow blood-brain barrier penetration. We ther efore propose that a drug combining the pharmacokinetic characteristics of, for example, ibuprofen with the COX-2 selectivity of rofecoxib is likely t o be a superior antiinflammatory analgesic.