title: Pravastatin transport across the hepatocyte canalicular membrane requires both ATP and a transmembrane pH gradient.
abstract: 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 [14C]-pravastatin (0.3 mumol), 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 Vmax was much lower than corresponding values in SD rats. This coincided well with the marked reduction in vivo biliary excretion of pravastatin in jaundiced rats.
authors.affiliation: Second Department of Internal Medicine, Kinki University School of Medicine, Osaka, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Adachi
authors.forename: Y
authors.initials: Y
authors.lastname: Okuyama
authors.forename: H
authors.initials: H
authors.lastname: Miya
authors.forename: H
authors.initials: H
authors.lastname: Matsusita
authors.forename: M
authors.initials: M
authors.lastname: Kitano
authors.forename: T
authors.initials: T
authors.lastname: Kamisako
authors.forename: T
authors.initials: T
authors.lastname: Yamamoto
mesh_terms: D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D001663:Bilirubin / Q000652:urine; D001692:Biological Transport; D002462:Cell Membrane / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics; D006859:Hydrogen / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D007565:Jaundice / Q000235:genetics / Q000652:urine; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D017035:Pravastatin / Q000493:pharmacokinetics*; D051381:Rats; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley
chemical_list: D004791:Enzyme Inhibitors; D006859:Hydrogen; D000255:Adenosine Triphosphate; D017035:Pravastatin; D001663:Bilirubin