Pharmacokinetic–pharmacodynamic modeling considering spinal and peripheral actions of nonsteroidal antiinflammatory drugs to optimize the treatment of inflammation-induced pain

Abstract

It has been documented that nonsteroidal antiinflammatory drugs (NSAIDs) exhibit pharmacological actions at both the peripheral and central levels. However, the actual participation of the mechanisms of action elicited at different anatomical sites after systemic NSAID administration is not clear. To gain further knowledge on this issue, the aim of the present work is to study the pharmacodynamics and pharmacokinetics of diclofenac, a NSAID prototype, using an integrative approach. We have previously documented that local diclofenac administration at the site of injury induces antinociception in the formalin test, as well as in the pain-induced functional impairment model in the rat. This effect is reduced by nitric oxide (NO) and cyclic GMP synthesis inhibitors, as well as by potassium channel blockers [1,2]. We therefore assayed the effect of oral (systemic) diclofenac in the formalin test after pretreatment with either NG-nitro-L-arginine Methyl ester (L-NAME), a NO synthesis blocker, or glibenclamide, a potassium channel blocker, given by two routes of administration: locally at the site of injury and intrathecally. L-NAME and glibenclamide given by these two routes significantly reduced oral diclofenac antinociception. These results suggest that, after systemic administration, effective diclofenac concentrations are achieved at the site of injury as well as at the spinal cord, and that in these two sites of action there is a participation of the L-arginine–NO–cyclic GMP–potassium channel pathway. In a second series of experiments, diclofenac was administered locally at the site of injury (peripheral location), intrathecally, and simultaneously at the site of injury, intrathecally. Isobolographic analysis showed that there is an additive interaction between the effects at the peripheral and spinal levels. It is then likely that, after systemic administration, the observed antinociceptive effect is the result of the sum of peripheral and central mechanisms. Thus, effective diclofenac concentrations at central sites achieved after systemic administration probably are considerably lower that those required to observe an antinociceptive effect after direct injection, due to the interaction of mechanisms elicited at different anatomical locations. Therefore, from a pharmacokinetic point of view, the various central and peripheral sites of action can be considered as the affected compartment. In a third experimental series, the pharmacokinetics and antinociceptive effect of diclofenac was assayed in the pain-induced functional impairment model in the rat, which allows a simultaneous determination of antinociception and blood drug concentration [3]. It appeared that there was no direct relationship between diclofenac in blood and antinociception. Antinociception, however, was significantly related to affect compartment concentrations estimated by pharmacokinetic–pharmacodynamic modeling, consistently with the earlier described pharmacodynamic results. Computer simulations using the derived pharmacokinetic–pharmacodynamic model showed that an oral formulation of diclofenac yielding a very fast absorption, and hence a high blood concentration peak, can optimize drug transfer to the affected compartment, resulting in a fast-onset, long-lasting antinociceptive response. Our results show that the study of NSAID pharmacodynamics and pharmacokinetics using an integrative approach is useful for the characterization of the mechanisms of action involved after systemic drug administration, yielding information that allows the optimization of dosing regimens.