Tissue human liver slices

If human metabolism studies with radiolabeled drug have not been performed prior to the conduct of reaction phenotyping studies, the initial experiments should use as complete an in vitro test system as possible, depending on the drug (e.g., tissue homogenates, liver slices, hepatocytes, etc.). 

These results demonstrate that, at the concentration used, PBO did not induce UDS in cultured human liver slices. The fact that the three known gero-toxins did produce a significant increase in UDS is testament to the functional viability of the huttian tissue used in this study, as all three compounds have been shown to undergo metabolic activation by human liver cytochrome P-450 isoenzymes (Gonzalez es a ., 1991),... 

Twombly and Taylor (1942) demonstrated that estradiol-l7/8 is inactivated more slowly by human liver than by rat or mouse liver they also examined a series of human carcinoma tissues, but could find no relation between the type of carcinoma and its ability to metabolize cstradiol-17/3. Lieberman and his colleagues used a colorimetric method to study the metabolism of estrone, cstradiol-17/3, and estriol in liver slices from the rat (Lieberman et al., 19.52) and from man (Tagnon et al., 1952). In 3 hours at 37°C,, 300 mg of rat liver slices metabolized 50 /xg of estradiol-17/3, 53 Hg of estrone, and 21 /xg of estriol (Lieberman et al., 1952). On the basis of the in vitro experiments with human liver slices, a human liver (mean weight 1.500 gm) should be able to inactivate 1.15 gm of estradiol-17/3 in 24 hours (Tagnon el al., 1952). 

P. Olinga, D. K. F. Meijer, M. J. H. Slooff, and G. M. M. Groothuis, Liver slices in in vitro pharmacotoxicology with special reference to the use of human liver tissue, Toxicol. In Vitro 72 77-100 (1998). 

If metabolism in animal models is extensive or the generated metabolite(s) is shown to have toxic effects, in vitro metabolism studies using isolated P-450 isozymes, tissue homogenates containing the microsomal fraction, hepatocytes, and liver slices are commonly conducted to determine if the extent of metabolism and the metabolite profile is similar for animals and humans. The results from these in vitro metabolism comparison studies can be used to select the animal models for definitive development studies that have similar metabolism profiles to humans. 

Rodrigues, A.D. Mulford, D.J. Lee, R.D. Surber, B.W. Kukulka, M.J. Ferrero, J.L. Thomas, S.B. Shet, M.S. Estabrook, R.W. In vitro metabolism of terfenadine by a purified recombinant fusion protein containing cytochrome P4503A4 and NADPH-P450 reductase. Comparison to human liver microsomes and precision-cut liver tissue slices. Drug Metab.Dispos., 1995, 23, 765-775... 

Liver slices have all the advantages of primary hepatocytes. In addition, the complete hepatic architecture is maintained so that sequential pathways that potentially involve several cells can also be studied. The limitation with liver slices is that they cannot be stored for long and not much work has been done to validate their use in enzyme induction. It is also very important to study a range of samples from different livers to obtain representative results. Human liver samples should be characterized as fully as possible with regard to gender, age, medical and drug history, and metabolic activity. Liver tissue samples should be obtained as soon as possible after surgery and stored rapidly at -80°C. 

In vitro models used for early screening for potential hep-atotoxic liability are predominantly based on single ceU systems or on human tissue preparations. Liver homogenates, microsomes, and slices can all be prepared from human tissue obtained as surgical by-products, which are more readily available as a resource than in the past. While such models provide valuable insights into the metabolism and covalent binding of new compounds, it is difficult to estimate the propensity for cytotoxicity directly, and consequently most attention is now focussed on the use of intact cell models. 

Nave R, Fisher R, Zech K (2006) In vitro metabolism of ciclesonide in human lung and liver precision-cut tissue slices. Biopharm Drug Dispos 27 197-207. 

During preclinical development the metabolite structures of potential new drug candidates are typically identified via in vitro tools such as subcellular liver fractions (microsomes, S9), expressed human enzymes, or cellular systems (e.g., hepatocytes, tissue slices) [25]. The metabolism observed in the different systems is compared across species, with the aim that all the metabolites formed in human in vitro systems can also be identified in the systems originating from the animal species used in major toxicity studies. 

---