title: Pharmacokinetic-pharmacodynamic modeling of diclofenac in normal and Freund's complete adjuvant-induced arthritic rats.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors: Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
authors: Jing
authors: J
authors: Zhang
authors: Pei
authors: P
authors: Li
authors: Hai-fang
authors: HF
authors: Guo
authors: Li
authors: L
authors: Liu
authors: Xiao-dong
authors: XD
authors: Liu
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000503:physiopathology; D004008:Diclofenac / Q000493:pharmacokinetics / Q000494:pharmacology*; D015232:Dinoprostone / Q000097:blood; D004195:Disease Models, Animal; D005620:Freund's Adjuvant / Q000633:toxicity; D007124:Immunoenzyme Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D008070:Lipopolysaccharides; D004008:Diclofenac; D005620:Freund's Adjuvant; D015232:Dinoprostone