EFFECT OF HYPOALBUMINEMIA ON THE DISPOSITION OF THEOPHYLLINE - COMPARATIVE-STUDY WITH SPRAGUE-DAWLEY RATS AND A MUTANT SPRAGUE-DAWLEY HYPERLIPIDEMIC STRAIN WITH HYPOALBUMINEMIA

We demonstrated the effect of hypoalbuminemia on theophylline disposit ion in rats. The pharmacokinetic parameters in Sprague-Dawley rats (SD Rs) were compared with those in spontaneously hyperlipidemic rats (HLR s), which had approximately one half the serum albumin concentration o f the SDRs, after a single 10 mg/kg injection (iv) of theophylline. Th eophylline clearance (CL) in the HLRs was increased 1.6-fold, and the AUC was decreased by 36%. Although the elimination t1/2 was not signif icantly different between the two types of rats, the distribution volu me (V-d) was increased significantly in the HLRs, compared with the SD Rs, The free theophylline concentration in the SDRs was one half of th e total concentration. In contrast, the free theophylline concentratio n in the HLRs was approximately equal to the total concentration. The enzymatic activities and apoprotein expression levels of CYP1A were de creased significantly in the HLRs, compared with the SDRs, The total t heophylline CL was increased in HLRs with hypoalbuminemia, even though they exhibited lower enzymatic activity and CYP1A expression than did the SDRs, Because the unbound fraction and V-d of theophylline in HLR s were much larger than those in SDRs, we conclude that hypoalbuminemi a may contribute to an increase in the V-d and a decrease in the CL fo r theophylline.