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      Pharmacokinetic-pharmacodynamic modeling of diclofenac in normal and Freund's complete adjuvant-induced arthritic rats

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          Abstract

          Aim:

          To characterize pharmacokinetic-pharmacodynamic modeling of diclofenac in Freund's complete adjuvant (FCA)-induced arthritic rats using prostaglandin E 2 (PGE 2) as a biomarker.

          Methods:

          The pharmacokinetics of diclofenac was investigated using 20-day-old arthritic rats. PGE 2 level in the rats was measured using an enzyme immunoassay. A pharmacokinetic-pharmacodynamic (PK-PD) model was developed to illustrate the relationship between the plasma concentration of diclofenac and the inhibition of PGE 2 production. The inhibition of diclofenac on lipopolysaccharide (LPS)-induced PGE 2 production in blood cells was investigated in vitro.

          Results:

          Similar pharmacokinetic behavior of diclofenac was found both in normal and FCA-induced arthritic rats. Diclofenac significantly decreased the plasma levels of PGE 2 in both normal and arthritic rats. The inhibitory effect on PGE 2 levels in the plasma was in proportion to the plasma concentration of diclofenac. No delay in the onset of inhibition was observed, suggesting that the effect compartment was located in the central compartment. An inhibitory effect sigmoid I max model was selected to characterize the relationship between the plasma concentration of diclofenac and the inhibition of PGE 2 production in vivo. The I max model was also used to illustrate the inhibition of diclofenac on LPS-induced PGE 2 production in blood cells in vitro.

          Conclusion:

          Arthritis induced by FCA does not alter the pharmacokinetic behaviors of diclofenac in rats, but the pharmacodynamics of diclofenac is slightly affected. A PK-PD model characterizing an inhibitory effect sigmoid I max can be used to fit the relationship between the plasma PGE 2 and diclofenac levels in both normal rats and FCA-induced arthritic rats.

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          Most cited references29

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          Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs.

          J R Vane (1971)
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            COX-dependent mechanisms involved in the antinociceptive action of NSAIDs at central and peripheral sites.

            Despite the diverse chemical structure of aspirin-like drugs, the antinociceptive effect of NSAIDs is mainly due to their common property of inhibiting cyclooxygenases involved in the formation of prostaglandins. Prostaglandins are potent hyperalgesic mediators which modulate multiple sites along the nociceptive pathway and enhance both transduction (peripheral sensitizing effect) and transmission (central sensitizing effect) of nociceptive information. Inhibition of the formation of prostaglandins at peripheral and central sites by NSAIDs thus leads to the normalisation of the increased pain threshold associated with inflammation. The contribution of peripheral and central mechanisms to the overall antinociceptive action of NSAIDs depends on several factors including the location of the targets of drug action, the site of drug delivery and the uptake and distribution to the site of action. The present work reviews the data on the regulation and location of cyclooxygenases at central and peripheral sites of the nociceptive pathway and focuses on the role of COX in the generation and maintenance of pain hypersensitivity. Experimental and clinical evidences are used to evaluate the significance of the peripheral and central antihyperalgesic effects of NSAIDs.
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              Origins of prostaglandin E2: involvements of cyclooxygenase (COX)-1 and COX-2 in human and rat systems.

              Prostaglandin (PG) E2 is a major cyclooxygenase (COX) product at inflammatory sites where it contributes to local increases in blood flow, edema formation, and pain sensitization. Using rats in vivo and rat and human blood in vitro, we have examined the roles of COX-1 and COX-2 in the production of PGE2. In anesthetized rats treated with bacterial lipopolysaccharide (LPS) to induce the expression of COX-2, the marked increase in PGE2 production that followed bolus intravenous injection of arachidonic acid (3 mg x kg(-1)) was strongly inhibited by diclofenac but largely unaffected by the COX-2-selective inhibitor DFP (5,5- dimethyl-3-(2-propoxy)-4-methanesulfonylphenyl)-2(5H)-furanone). In rat blood in vitro, aspirin strongly inhibited the production of PGE2 that followed either acute exposure to calcium ionophore, A23187 (calcimycin) (50 microM, 15 min), or incubation with LPS for 18 h. In contrast, human whole blood only produced significant levels of PGE2 when incubated with LPS. Rat leukocytes expressed COX-2 and produced PGE2 when exposed to LPS but not when acutely stimulated with A23187. Rat platelets, but not human platelets, also produced significant amounts of PGE2 when acutely stimulated with A23187. These data show that when exposed to an inflammatory stimulus, rat whole blood produces increased levels of PGE2 through induction of COX-2 in blood leukocytes. Rat blood, unlike human blood, may also produce copious amounts of PGE2 via the actions of COX-1 enzyme constitutively present in platelets. These data may well explain why in rats COX-2-selective inhibitors have been reported not to produce the full anti-inflammatory effects associated with standard nonsteroid anti-inflammatory drugs.
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                Author and article information

                Journal
                Acta Pharmacol Sin
                Acta Pharmacol. Sin
                Acta Pharmacologica Sinica
                Nature Publishing Group
                1671-4083
                1745-7254
                November 2012
                30 July 2012
                : 33
                : 11
                : 1372-1378
                Affiliations
                [1 ]Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing 210009, China
                Author notes
                Article
                aps201267
                10.1038/aps.2012.67
                4011350
                22842736
                a7c75e9b-04b0-4851-9780-f4ba4c244c83
                Copyright © 2012 CPS and SIMM
                History
                : 13 March 2012
                : 09 May 2012
                Categories
                Original Article

                Pharmacology & Pharmaceutical medicine
                pharmacokinetic-pharmacodynamic modeling,diclofenac,prostaglandin e2 (pge2),freund's complete adjuvant (fca)-induced arthritis,lipopolysaccharide,blood cells

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