Pharmacokinetics of dexamethasone in a rat model of rheumatoid arthritis.
Dexamethasone (DEX) is often given for the treatment of rheumatoid arthritis and clinical dosing regimens of DEX have often been based empirically. This study tests whether the inflammation processes in a rat model of rheumatoid arthritis alters the clearance and volume of distribution of DEX when compared with healthy controls. Groups of healthy and arthritic male Lewis rats received either a low (0.225 mg/kg) or high (2.25 mg/kg) intramuscular dose of DEX. Arthritis was induced by intradermal injection of type II porcine collagen in incomplete Freund's adjuvant emulsion at the base of the tail. DEX was dosed in the arthritic animals 22 days post arthritis induction. Plasma DEX concentrations were determined by HPLC. Plasma concentration versus time data were analysed by non-compartmental analysis and pharmacokinetic model fitting using the population pharmacokinetic software NONMEM V. A linear bi-exponential pharmacokinetic model with extravascular input described the data for both healthy and arthritic animals. Clearance was the only parameter determined statistically different between both groups (healthy=1.05 l/h/kg, arthritic=1.19 l/h/kg). The steady-state volume of distribution for both groups was 4.85 l/kg. The slight difference in clearance was visibly undetectable and unlikely to produce meaningful changes in DEX disposition in arthritic rats.
Earp
Justin C
JC
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York 14260, USA.
Pyszczynski
Nancy A
NA
Molano
Diana S
DS
Jusko
William J
WJ
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D024043:Collagen Type II; D003907:Dexamethasone / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D007273:Injections, Intramuscular; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D013552:Swine; D014018:Tissue Distribution
D000893:Anti-Inflammatory Agents; D024043:Collagen Type II; D003907:Dexamethasone