D. Nakai et al., Human liver-specific organic anion transporter, LST-1, mediates uptake of pravastatin by human hepatocytes, J PHARM EXP, 297(3), 2001, pp. 861-867
Citations number
29
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
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-meth
ylglutaryl 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 (K-m) of 11
.5 +/- 2.2 muM. The uptake of pravastatin was temperature-dependent and was
inhibited by estradiol-17 beta -D-glucuronide, taurocholic acid, bromosulf
ophthalein, and simvastatin acid, but not by p-aminohippurate. Estradiol-17
beta -D-glucuronide competitively inhibited pravastatin uptake with an inh
ibition constant comparable to the K-m value for estradiol-17 beta -D-glucu
ronide transport, indicating that a common transporter mediates the transpo
rt of pravastatin and estradiol-17 beta -D-glucuronide in human hepatocytes
. The results obtained with human hepatocytes agreed with those obtained wi
th LST-1 expressing Xenopus oocytes. Oocytes microinjected with human liver
polyadenylated mRNA showed Na+-independent uptake of pravastatin and estra
diol-17 beta -D-glucuronide. A simultaneous injection of LST-1 antisense ol
igonucleotides completely abolished this uptake. Expression of LST-1 was im
munohistochemically demonstrated in the human hepatocytes, but not in Hep G
2 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.