The applicability of rat and human liver slices to the study of mechanisms of hepatic drug uptake.
In the present study we investigated the applicability of the liver slice model to study mechanisms of drug uptake. Four model compounds were investigated that enter hepatocytes via entirely different membrane transport mechanisms. Rhodamine B (RB), which enters hepatocytes by passive diffusion, was homogeneously distributed throughout the rat liver slice (250 microm thickness) within 5 min, indicating that the penetration rate into the slice and the diffusion rate into the cells are rapid. In contrast, lucigenin (LU), which is taken up by hepatocytes through adsorptive endocytosis, was detected in the inner cell layers after 15 min. Digoxin uptake into the slice showed a temperature-dependent component and was stereoselectively inhibited by quinine, which is compatible with the involvement of a carrier-mediated uptake mechanism. The neo-glycoalbumin Lactose(27)-Human Serum Albumin (Lact(27)-HSA) and the negatively charged Succinylated-Human Serum Albumin (Suc-HSA) entered the slices and were taken up temperature-dependently into hepatocytes and endothelial cells, respectively. The liver slice preparation is a valuable tool to investigate the mechanisms of cellular uptake of drugs. Moreover, the precision-cut liver slices offer the unique possibility to study both hepatocyte and endothelial cell function in human and rat liver.
Olinga
P
P
Department of Pharmacokinetics and Drug Delivery, University Centre for Pharmacy, Groningen University Institute for Drug Exploration, Ant. Deusinglaan 1, 9713 AV Groningen, Netherlands. p.olinga@farm.rug.nl
Hof
I H
IH
Merema
M T
MT
Smit
M
M
de Jager
M H
MH
Swart
P J
PJ
Slooff
M J
MJ
Meijer
D K
DK
Groothuis
G M
GM
D000156:Aconitic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000166:Acridines / Q000493:pharmacokinetics; D000818:Animals; D004077:Digoxin / Q000493:pharmacokinetics; D004563:Electrochemistry; D004727:Endothelium / Q000378:metabolism; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010599:Pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D012235:Rhodamines / Q000493:pharmacokinetics; D012709:Serum Albumin / Q000493:pharmacokinetics; D000075462:Serum Albumin, Human; D014018:Tissue Distribution
D000166:Acridines; D005456:Fluorescent Dyes; D012235:Rhodamines; D012709:Serum Albumin; C108785:polyaconitylated human serum albumin; C034877:succinylalbumin; C033472:10,10'-dimethyl-9,9'-biacridinium; D004077:Digoxin; D000156:Aconitic Acid; C029773:rhodamine B; D000075462:Serum Albumin, Human