Limited Effect of Intravenously Administered Indoxyl Sulfate, a Uremic Toxin, on the Hepatic Transport of Pravastatin in Normal Rats

It is generally understood that under seriously impaired renal function a variety of uremic toxins accumulate in the body at greater plasma levels, with indoxyl sulfate (IS) typical of such uremic toxins. Elevated IS levels leads to the induction of various unfavorable events such as progression to renal failure, and cardiovascular and bone toxicities. IS accumulation is attributed primarily to the fact that IS is a potent substrate of organic anion transporter (OAT) and OAT3 presents on the basal membrane of the renal epithelial cells. Moreover, IS is a highly protein-bound compound. Based on these characteristics, IS is considered to be associated with the occurrence of clinically relevant pharmacokinetic drug interactions in the patients with impaired renal function.

This study sought to clarify whether IS exerted a potent modulating effect on the hepatic transport of pravastatin, which is a substrate of both organic anion transporting peptides (OATPs) and multidrug resistance-associated protein (Mrp) 2 in rats. First, the authors investigated the time course of plasma IS levels after intravenous administration to rats with normal renal function at two doses. Next, they evaluated the effect of IS on the clearance of pravastatin from rat plasma after intravenous administration.

The results indicated that when IS was administered intravenously to the normal rats at a dose of 120 μmol/kg; plasma IS levels were approximately 600 μM after 2 min and 100 μM after 120 min. In rats with acute renal failure (ARF) induced by cisplatin, the area under the curve (AUC) was more than 2.5-fold greater compared with that in the normal rats, indicating that IS accumulated in ARF rats. Intravenously administered pravastatin almost disappeared from the plasma by 60 min post-administration and approximately 55% of dose was excreted in the bile within 60 min.

In conclusion, the present results suggest that single intravenous administration of IS to normal rats causes only a very limited modulating effect on the transport mediated by OATPs and Mrp2 present in hepatocytes.

Article by Hideyuki Suga, et al, from Health Sciences University of Hokkaido, Ishikari-Tobetsu, Japan.

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