Effect of cold and warm ischaemia on drug metabolism in isolated hepatocytes and slices from human and monkey liver.
1. The influence of short-term cold storage in University of Wisconsin organ preservation solution (UW) on the ability to metabolize lidocaine, testosterone and 7-ethoxycoumarin in isolated human and cynomolgus monkey (Macaca fascicularis) hepatocytes and liver slices has been investigated. 2. The human liver tissue was obtained from two different sources, i.e. healthy liver tissue from patients undergoing partial hepatectomy because of metastases of colorectal carcinoma (PH livers) and donor tissue remaining as surgical waste after reduced size or split liver transplantation (Tx livers). Tx livers were perfused in situ with ice-cold UW avoiding warm ischaemia. This in contrast with PH livers, where the operation caused warm ischaemia for 5-90 min. 3. Liver slices and hepatocytes from cynomolgus monkey liver showed comparable metabolic rates for the substrates tested, indicating that all hepatocytes in the slice are participating in the biotransformation of the substrates. These monkey liver preparations can be stored up to 18 h with only a slight loss of their metabolic capacity. 4. Liver slices and isolated hepatocytes from the Tx livers as well as isolated cells from the PH livers could also be stored up to 18 h without losing metabolic capacity. However, for liver slices prepared from PH livers cold storage is not recommended, because metabolic function was reduced by approximately 40% after 18 h.
Olinga
P
P
Groningen Institute for Drug Studies, Department of Pharmacokinetics and Drug Delivery, University Centre for Pharmacy, The Netherlands.
Merema
M T
MT
Hof
I H
IH
De Jager
M H
MH
De Jong
K P
KP
Slooff
M J
MJ
Meijer
D K
DK
Groothuis
G M
GM
D000818:Animals; D003080:Cold Temperature; D003374:Coumarins / Q000378:metabolism*; D015925:Cryopreservation; D006358:Hot Temperature; D006801:Humans; D066298:In Vitro Techniques; D007511:Ischemia / Q000378:metabolism*; D008012:Lidocaine / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008252:Macaca fascicularis; D009926:Organ Preservation; D013739:Testosterone / Q000378:metabolism*
D003374:Coumarins; C017299:7-ethoxycoumarin; D013739:Testosterone; D008012:Lidocaine