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

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.

An LC–MS/MS method for the quantification of diclofenac sodium in dairy cow plasma and its application in pharmacokinetics studies

“…Zhang, Li, Guo, Liu, and Liu () reported that the IC 50 of DCF for inhibition of PGE 2 production in vivo was 0.5 ± 0.2 μg mL −1 . The mean plasma concentration of DCF was 512.92 ± 110.95 ng mL −1 24 h after i.m.…”

“…The results with exception of Rahal et al (2008) showed that DCF was rapidly and well absorbed in cows, sheep and pigs. Zhang, Li, Guo, Liu, and Liu (2012) reported that the IC 50 of DCF for inhibition of PGE 2 production in vivo was 0.5 ± 0.2 μg mL −1 . The mean plasma concentration of DCF was 512.92 ± 110.95 ng mL −1 24 h after i.m.…”

Ciprofloxacin blocked enterohepatic circulation of diclofenac and alleviated NSAID-induced enteropathy in rats partly by inhibiting intestinal β-glucuronidase activity

“…Concentrations of diclofenac in rat plasma and the incubation system were determined by HPLC with an ultraviolet detector, as previously described [32] with minor modifications. Briefly, for plasma samples, 50 μL plasma was spiked with 10 µL of 2 μg/mL chloroxazone as an internal standard and 100 µL acetonitrile.…”

Evaluation of a Postoperative Pain‐Like State on Motivated Behavior in Rats: Effects of Plantar Incision on Progressive‐Ratio Food‐Maintained Responding

“…30 min prior to operant experiments. The 5.6 mg/kg dose was chosen based on pilot data in our laboratory, and literature on diclofenac efficacy and potency against a range of nociceptive conditions [Euchenhofer et al, 1998;Yoshimi et al, 2010;Moller et al, 2012;Zhang et al, 2012].…”