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Vol. 297, Issue 3, 861-867, June 2001
Drug Metabolism and Pharmacokinetics Research Laboratories, Sankyo
Co., Ltd., Tokyo, Japan (D.N., R.N., Y.F., T.T., T.I., K.N.); and
Department of Neurophysiology, Tohoku University School of Medicine,
Sendai, Japan (T.A.)
Involvement of LST-1 (a human liver-specific transporter, also called
OATP2) as the major transporter in the uptake of pravastatin, a
3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, by human
liver was demonstrated. The hepatic uptake of pravastatin evaluated
using human hepatocytes was Na+-independent and reached
saturation with a Michaelis constant (Km) of
11.5 ± 2.2 µM. The uptake of pravastatin was
temperature-dependent and was inhibited by
estradiol-17
-D-glucuronide, taurocholic acid,
bromosulfophthalein, and simvastatin acid, but not by
p-aminohippurate. Estradiol-17-D-glucuronide competitively inhibited
pravastatin uptake with an inhibition constant comparable to the
Km value for
estradiol-17-D-glucuronide transport, indicating that a
common transporter mediates the transport of pravastatin and
estradiol-17-D-glucuronide in human hepatocytes. The
results obtained with human hepatocytes agreed with those obtained with
LST-1 expressing Xenopus oocytes. Oocytes microinjected
with human liver polyadenylated mRNA showed Na+-independent
uptake of pravastatin and estradiol-17-D-glucuronide. A
simultaneous injection of LST-1 antisense oligonucleotides completely abolished this uptake. Expression of LST-1 was immunohistochemically demonstrated in the human hepatocytes, but not in Hep G2 cells, which
showed very low uptake of pravastatin. Therefore, LST-1 was regarded as
a key molecule for pravastatin in liver-specific inhibition of
cholesterol synthesis, making pravastatin accessible to the target
enzyme, which would otherwise not be inhibited by this hydrophilic drug.
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