Naproxen (NPX) is used in the treatment of rheumatoid arthritis (RA) for alleviation of pain and inflammation. In view of the extensive albumin binding of NPX, this study investigates whether chronic inflammation and sex will influence the physiological albumin concentrations, plasma protein binding, and pharmacokinetics (PK) of NPX. The PK of NPX was evaluated in a rat model of RA (collagen-induced arthritis (CIA) in Lewis rats) and in healthy controls. These PK studies included: 1) NPX in female and male CIA rats that received 10, 25 or 50 mg/kg NPX intraperitoneally (IP), and 2) NPX in healthy female and male rats after IP dosing of NPX at 50 mg/kg. Plasma albumin concentrations were quantified by ELISA and protein binding assessed using ultrafiltration. The NPX concentrations in plasma and filtrates were determined by LC-MS/MS. Plasma concentration-time data of NPX were first assessed by non-compartmental analysis (NCA). Nonlinear PK as indicated by dose-dependent NCA clearances and distribution volumes was observed. A two-compartment model (2CM) with a first-order absorption process incorporating nonlinear protein binding in plasma and tissues jointly described the PK data of all groups. Saturable albumin binding accounts for the nonlinearity of NPX PK in all rats as well as part of the PK differences in arthritic rats. The CIA rats exhibited reduced albumin concentrations, reduced overall protein binding, and reduced clearances of unbound NPX, consistent with expectations during inflammation. The net effect of chronic inflammation was an elevation of the Cmax and AUC of unbound drug.
- The American Society for Pharmacology and Experimental Therapeutics