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 disposition in rats. The pharmacokinetic parameters in Sprague-Dawley rats (SDRs) were compared with those in spontaneously hyperlipidemic rats (HLRs), which had approximately one half the serum albumin concentration of the SDRs, after a single 10 mg/kg injection (iv) of theophylline. Theophylline clearance (CL) in the HLRs was increased 1.6-fold, and the AUC was decreased by 36%. Although the elimination t 1/4 was not significantly different between the two types of rats, the distribution volume (V(d)) was increased significantly in the HLRs, compared with the SDRs. The free theophylline concentration in the SDRs was one half of the total concentration. In contrast, the free theophylline concentration in the HLRs was approximately equal to the total concentration. The enzymatic activities and apoprotein expression levels of CYP1A were decreased significantly in the HLRs, compared with the SDRs. The total theophylline 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 HLRs were much larger than those in SDRs, we conclude that hypoalbuminemia may contribute to an increase in the V(d) and a decrease in the CL for theophylline.