Cellular distribution and handling of liver-targeting preparations in human livers studied by a liver lobe perfusion.
We developed and tested a novel method for perfusing parts of human liver to study uptake and handling of drug-targeting preparations. These preparations, designed for the treatment of liver fibrosis in man, have been extensively studied in animals, but little is known about the uptake and handling by human livers. Human liver tissue was obtained from livers procured from multiorgan donors and from cirrhotic livers of patients. To assess tissue viability, perfusate glutamate-oxalacetate-transaminase (GOT), glutamate-pyruvate-transaminase (GPT), and lactate dehydrogenase (LDH) levels were determined. To assess tissue functionality, the uptake of taurocholic acid and phase I and II metabolism of lidocaine and 7-hydroxycoumarin were determined. Uptake of a drug-targeting preparation was studied with Dexa10-HSA, which is designed for targeting of dexamethasone to nonparenchymal cells in the liver. During a 90-min perfusion period, no elevation of either GOT, GPT, or LDH was found. Both healthy control livers and cirrhotic livers showed phase I and II drug metabolism and functional taurocholic acid uptake. Studies with Dexa10-HSA revealed that 60 min after administration, 40% of the dose had been taken up by control livers and only 5% by cirrhotic livers. In control livers, Kupffer and endothelial cells had taken up Dexa10-HSA, whereas in cirrhotic livers only Kupffer cells were responsible for the uptake. Viability parameters and liver function tests clearly showed the applicability of this method. In the perfusion set-up, we showed uptake of the drug-targeting preparation Dexa10-HSA by healthy and cirrhotic human liver tissue, although the distribution patterns differed. This demonstrates the need to study new concepts in (diseased) human tissue.
Melgert
B N
BN
Groningen University Institute for Drug Exploration, Department of Pharmacokinetics and Drug Delivery, University of Groningen, The Netherlands. B.Mmelgert@farm.rug.nl
Olinga
P
P
Weert
B
B
Slooff
M J
MJ
Meijer
D K
DK
Poelstra
K
K
Groothuis
G M
GM
D000779:Anesthetics, Local / Q000378:metabolism; D002756:Cholagogues and Choleretics / Q000493:pharmacokinetics; D003907:Dexamethasone / Q000737:chemistry / Q000493:pharmacokinetics*; D005938:Glucocorticoids / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D008012:Lidocaine / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000502:physiology*; D010477:Perfusion; D012709:Serum Albumin; D013656:Taurocholic Acid / Q000493:pharmacokinetics; D014468:Umbelliferones / Q000378:metabolism
D000779:Anesthetics, Local; D002756:Cholagogues and Choleretics; D005938:Glucocorticoids; D012709:Serum Albumin; D014468:Umbelliferones; D013656:Taurocholic Acid; C031477:7-hydroxycoumarin; D003907:Dexamethasone; D008012:Lidocaine