Cellular distribution and handling of liver-targeting preparations in human livers studied by a liver lobe perfusion (vol 29, pg 361, 2001)

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.