EFFECT OF EXPERIMENTAL DIABETES-MELLITUS AND ARTHRITIS ON THE PHARMACOKINETICS OF HYDROXYCHLOROQUINE ENANTIOMERS IN RATS

Purpose. To study the effect of experimental diabetes and arthritis on the pharmacokinetics of hydroxychloroquine (HCQ) enantiomers in rats. Methods. The pharmacokinetic studies were carried out following admin istration of 40 mg/kg of racemic HCQ to diabetic, insulin-treated diab etic, adjuvant arthritic and control rats. Results, Renal (70% and 62% for R- and S-HCQ, respectively) and non-renal clearance (100% and 145 % for R-and S-HCQ, respectively) of HCQ enantiomers were significantly increased in diabetic rats. Diabetes-induced alterations in the dispo sition of HCQ were reversed by insulin treatment. In arthritic rats, s ystemic clearance (CL) of HCQ enantiomers was significantly reduced (1 .05 +/- 0.15 and 1.3 +/- 0.19 1/h/kg for R-and S-HCQ, respectively) co mpared to controls (1.69 +/- 0.32 and 1.93 +/- 0.34 1/h/kg for R-and S -HCQ, respectively). The fraction unbound of the R-and S-HCQ were 49.4 % and 50.5% lower in platelet rich plasma of arthritic rats compared t o healthy rats. Increased blood concentrations of HCQ enantiomers in a rthritic rats were significantly related to the degree of inflammation . Conclusions. Diabetes significantly increased the CL of both R-acid S-HCQ by increasing renal and non-renal clearance. Arthritis caused a significant decrease in CL of HCQ enantiomers through increased bindin g and a decreased intrinsic clearance. The effect of the diseases on t he pharmacokinetics of HCQ, however, was not stereoselective.