Comparison of intrinsic metabolic clearance in fresh and cryopreserved human hepatocytes

Abstract

1. We compared the intrinsic clearance (CL_int) of a number of substrates in suspensions of fresh and cryopreserved human hepatocytes from seven donors.

2. CL_int values for a cocktail incubation of phenacetin, diclofenac, diazepam, bufuralol, midazolam, and hydroxycoumarin were 4.9 ± 3.4, 18 ± 7.2, 5.1 ± 4.9, 6.3 ± 3.3, 9.8 ± 5.8 and 22 ± 14 μl min⁻¹/10⁶ cells, respectively, and they correlated well with corresponding CL_int values using cryopreserved hepatocytes from 25 different donors.

3. CL_int values of each cocktail substrate and 20 AstraZeneca new chemical entities were compared in fresh and cryopreserved hepatocytes from the same three donors. There was a statistically significant correlation between CL_int in fresh and cryopreserved hepatocytes for each of the three livers (p < 0.002) and the geometric mean of the ratio of fresh to cryopreserved CL_int values was 1.03.

4. In conclusion, the results add further support to the use of cryopreserved human hepatocytes as a screening model for the intrinsic clearance of new chemical entities.

Keywords::

• Human hepatocytes
• fresh
• cryopreserved
• intrinsic clearance
• drug metabolism
• drug development

Acknowledgements

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.