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Pravastatin transport across the hepatocyte canalicular membrane requires both ATP and a transmembrane pH gradient
Author(s) -
ADACHI YUKIHIKO,
OKUYAMA YOSHIFUMI,
MIYA HIROHISA,
MATSUSITA HIROAKI,
KITANO MOTOKAZU,
KAMISAKO TOSHINORI,
YAMAMOTO TOSHIO
Publication year - 1996
Publication title -
journal of gastroenterology and hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.214
H-Index - 130
eISSN - 1440-1746
pISSN - 0815-9319
DOI - 10.1111/j.1440-1746.1996.tb01706.x
Subject(s) - pravastatin , cotransporter , hepatocyte , endocrinology , hydroxymethylglutaryl coa reductase , medicine , excretion , chemistry , reductase , electrochemical gradient , membrane transport , in vivo , transmembrane protein , hmg coa reductase , biochemistry , membrane , biology , enzyme , cholesterol , in vitro , sodium , microbiology and biotechnology , organic chemistry , receptor
Hepatic excretion of non‐bile acid organic anions is reported to be ATP‐dependent and a defect of this transport has been reported in congenitally jaundiced rats, animal models of human Dubin‐Johnson syndrome. To investigate the effect of the transmembrane pH gradient on hepatocyte canalicular membrane transport of ATP‐dependent organic anions, uptake of pravastatin, a 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG CoA) reductase‐inhibiting organic anion, by hepatocyte canalicular membrane vesicles was observed in the presence or absence of transmembrane pH gradients. Uptake was assessed by a rapid filtration technique. ATP‐dependent pravastatin uptake was stimulated in the presence of a transmembrane pH gradient (in > out) in Sprague‐Dawley (SD) rats. Uptake was dependent on both pravastatin and ATP concentrations and showed saturation kinetics. After intravenous injection of [ 14 C]‐pravastatin (0.3 μmol), 81% of the dose was excreted in the bile within 35 min in SD rats, whereas only 20% was excreted in the bile in Eisai hyperbilirubinuria rats. ATP and the pH gradient also co‐stimulated the uptake of pravastatin in Eisai hyperbilirubinuria rats, although the K m was much higher and V max was much lower than corresponding values in SD rats. This coincided well with the marked reduction in in vivo biliary excretion of pravastatin in jaundiced rats.