TITLE:
Limited Effect of Intravenously Administered Indoxyl Sulfate, a Uremic Toxin, on the Hepatic Transport of Pravastatin in Normal Rats
AUTHORS:
Hideyuki Suga, Yuichi Ichimura, Satomi Otsuka, Kaori Sugaya, Masako Oda, Hiroshi Saitoh
KEYWORDS:
Indoxyl Sulfate, Pravastatin, Drug Interaction, Hepatic Transport, Biliary Excretion
JOURNAL NAME:
Pharmacology & Pharmacy,
Vol.9 No.7,
July
27,
2018
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.