Abstract
Indoxyl sulfate (IS) is a typical uremic toxin that extensively accumulates in the plasma of patients with seriously impaired renal function. This study seeks to clarify whether IS exerts 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. When IS is administered intravenously to the normal rats at a dose of 120 μmol/kg; plasma IS levels are 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 accumulates 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. This result suggested that pravastatin was efficiently taken up from the sinusoid into hepatocytes via rat OATPs on the sinusoidal membrane and preferentially transported in the bile mediated by Mrp2 on the canalicular membrane. IS administered intravenously at a dose of 120 μmol/kg caused neither an increase in plasma pravastatin levels nor a decrease in its biliary excretion. In conclusion, the present results demonstrate that single intravenous administration of IS does not interfere with the hepatic transport of pravastatin directly in vivo, which is at variance with the results of previous in vitro studies.
Highlights
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 [1]
The results of this study showed that intravenously administered pravastatin disappeared very quickly from the plasma in normal rats (Figure 2) and that more than 50% of the pravastatin was excreted in the bile within first 60 min post-administration (Figure 3)
These results strongly suggested that pravastatin was taken up very efficiently from the sinusoid into hepatocytes and transported into the bile across the canalicular membranes
Summary
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 [1]. 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. There has been a good deal of interest in the alteration of nonrenal drug clearance in patients with severe chronic kidney disease (CKD) [7]. In this context, the modulating effects of uremic toxins on drug metabolism and transport have been emphasized [8] [9]. If IS directly interferes with OATP-mediated statin transport in such patients, it is likely that elevated IS levels in patient plasma are responsible for the adverse events induced by statins. In order to assess this, we investigated whether intravenously administered IS can modulate the hepatic transport of pravastatin in normal rats in vivo
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call