A cell assay can make midazolam metabolism look weak or strong depending on which liver model the researchers use. The choice matters when a toxicologist evaluates whether an experiment supports a proposed drug interaction.
Berger and colleagues applied the same set of probe drugs to HepG2 cells, HepaRG cells and primary human hepatocytes in two-dimensional and three-dimensional culture. The two primary cultures came from the same donor batch. Midazolam served as the CYP3A4 probe, and the team measured formation of its hydroxylated metabolite by LC–MS/MS. Table 2 shows much lower basal metabolite formation in HepG2 than in either primary-cell model or HepaRG.
The researchers measured enzyme messenger RNA and metabolite formation separately. Those readouts answer different questions about expression and activity. When weighing an interaction study, identify the cell system, the probe and the measured product. The comparison can help establish how informative a laboratory model is. Estimating a person’s clearance requires human pharmacokinetic evidence.
Berger et al., Comparison of Liver Cell Models Using the Basel Phenotyping Cocktail