title: Examination of the pharmacodynamics and pharmacokinetics of a diclofenac poly(lactic-co-glycolic) acid nanoparticle formulation in the rat.
abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) are assembled into two categories; cyclooxygenase (COX-1) sparing inhibitors of COX-2 and non-selective NSAIDs. Diclofenac (DICLO) is a non-selective NSAID that has been linked to serious side effects including gastric ulcers and renal injury. In this study, we examine the effect of poly(lactic-co-glycolic) acid nanoformulation on DICLO-associated adverse events and pharmacokinetics using a nanoparticle (NP) formulation previously developed in our laboratory.
  
  
  
  Rats were administered a single dose of methylcellulose (VEH), blank NP, DICLO (10 mg/kg), or a DICLO-NP suspension equivalent to the DICLO dose. Urinary and blood parameters were measured at baseline and following treatment. Duodenal and gastric prostaglandin E2 (PGE2) and duodenal myeloperoxidase (MPO) were collected to assess inflammation at 24 hrs post-treatment.
  
  
  
  The mean percent change from baseline in sodium excretion rate (µmol/min/100 g body weight) differed significantly from VEH in the NP (p < 0.0001), DICLO (p < 0.0001), and DICLO-NP (p = 0.0001) groups. The differences among groups did not reach significance for plasma sodium or potassium concentrations, potassium excretion rate, gastric PGE2, or intestinal biomarker concentrations. Regarding renal histopathology, DICLO produced considerably more necrosis compared to VEH; while DICLO-NP did not elicit notable differences from VEH.
  
  
  
  Our results suggest that over the duration and dosage examined, DICLO-NP may reduce renal necrosis without influencing other side effects or drug characteristics.
authors.affiliation: Department of Pharmaceutical Sciences, Gatton College of Pharmacy, East Tennessee State University, Johnson City, TN, USA. harirfor@etsu.edu.
authors.forename: S
authors.initials: S
authors.lastname: Harirforoosh
authors.forename: K O
authors.initials: KO
authors.lastname: West
authors.forename: D E
authors.initials: DE
authors.lastname: Murrell
authors.forename: J W
authors.initials: JW
authors.lastname: Denham
authors.forename: P C
authors.initials: PC
authors.lastname: Panus
authors.forename: G A
authors.initials: GA
authors.lastname: Hanley
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics*; D051546:Cyclooxygenase 2; D004008:Diclofenac / Q000493:pharmacokinetics*; D006018:Glycols; D007674:Kidney Diseases / Q000139:chemically induced*; D053758:Nanoparticles; D051381:Rats
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D006018:Glycols; D004008:Diclofenac; D051546:Cyclooxygenase 2