Inhibition of prostaglandin synthesis in vivo by nonsteroid anti-inflammatory drugs: Evidence for the importance of pharmacokinetics

Abstract

A variety of acidic and non-acidic compounds are potent inhibitors of prostaglandin (PG) synthesis in vitro. However, only a few, namely the acidic nonsteroid anti-inflammatory drugs (NSAID) are useful anti-inflammatory analgesics in the clinic. Since inhibition of PG-synthesis is believed to be the main target of NSAID in inflammation this superiority of acidic compounds remains unexplained. We have considered that one explanation could be that only acidic NSAID appear in high concentrations in inflamed tissue to inhibit PG-synthesis sufficiently. To test this hypothesis the following experiments were carried out: (A) PG-synthesis and its inhibition by acidic and non-acidic NSAID was measured in vivo at the site of inflammation. It was found that in therapeutic doses only acidic NSAID were capable to reduce PG-synthesis significantly. (B) Measurement of drug concentration in inflamed tissue showed that only acidic NSAID were found in significantly higher concentrations in inflamed than in control tissue. From these observations it is concluded that a specific pharmacokinetic behaviour of acidic NSAID leading to high concentrations in inflamed tissue is a decisive aspect of their anti-inflammatory action.

Predictability of the clinical potency of NSAIDs from the preclinical pharmacodynamics in rats

“…The analysis also supports the observation that NSAIDs with higher pKa's exhibit greater antiinftammatory potency, as already suggested by Brune et al [87]. It has been hypothesized that increasing the pKa of NSAIDs will increase their unionized concentrations in the extracellular fluid, which in turn will increase the diffusion of drug molecules to intracellular sites of action [6].…”

A chronic pain: Inflammation-dependent chemoreceptor adaptation in rat carotid body

“…In addition, this drug has been shown to block the nuclear translocation of the transcription factor, nuclear factor kappa beta (NF-κβ), which mediates cytokine production including IL-1β, TNFα and IL-6 (Scheuren et al 1998). A potentially important physical property of ibuprofen is its tendency to partition into low pH compartments, such as local areas of inflammation (Brune and Lanz 1985; Brune et al 1976). The steroid, dexamethasone, operates via nuclear receptors to block the cascade of cytokine synthesis and release.…”

Integration of Pharmacokinetics, Pharmacodynamics, and Toxicokinetics in Rational Drug Development

“…Brune et al (1976) have suggested that pKa and plasma protein binding characteristics may predict AI activity for cyclooxygenase inhibitors. Although a clear-cut reason for this phenomenon is not known, it can be speculated that highly bound AI drugs reach inflarnmed tissue sites to exert their pharmacologic effect through the extravasation of proteins resulting from a change in capillary permeability at the site of inflammation.…”