Bn. Melgert et al., Cellular distribution and handling of liver-targeting preparations in human livers studied by a liver lobe perfusion, DRUG META D, 29(4), 2001, pp. 361-367
We developed and tested a novel method for perfusing parts of human liver t
o study uptake and handling of drug-targeting preparations. These preparati
ons, designed for the treatment of liver fibrosis in man, have been extensi
vely 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 v
iability, perfusate glutamate-oxalacetate-transaminase (GOT), glutamate-pyr
uvate-transaminase (GPT), and lactate dehydrogenase (LDH) levels were deter
mined. To assess tissue functionality, the uptake of taurocholic acid and p
hase I and II metabolism of lidocaine and 7-hydroxycoumarin were determined
. Uptake of a drug-targeting preparation was studied with Dexa(10)-HSA, whi
ch is designed for targeting of dexamethasone to nonparenchymal cells in th
e 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. Stud
ies with Dexa(10)-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 Dexa(10)-HSA,
whereas in cirrhotic livers only Kupffer cells were responsible for the up
take. Viability parameters and liver function tests clearly showed the appl
icability of this method. In the perfusion set-up, we showed uptake of the
drug-targeting preparation Dexa(10)-HSA by healthy and cirrhotic human live
r tissue, although the distribution patterns differed. This demonstrates th
e need to study new concepts in (diseased) human tissue.