Cytochrome P450 inhibition by common ABC transporter inhibitor in human microsomes and cryopreserved hepatocytes.
| Inhibitor | Inhibition of Loperamide Metabolism | Inhibition of Midazolam Metabolism | ||||
|---|---|---|---|---|---|---|
| Liver Microsomes | Cryopreserved Hepatocytes | Fold Difference (mic/hep) | Liver Microsomes | Cryopreserved Hepatocytes | Fold Difference (mic/hep) | |
| IC50 (μM) | IC50 (μM) | |||||
| Cyclosporin A | 15.3 ± 1.2 | 26.3 ± 1.6 | 0.6 | 67.8 ± 2.5 | 65.8 ± 1.4 | 1.0 |
| Elacridar | 17.8 ± 1.4 | 62.0 ± 1.6* | 0.3 | 31.7 ± 1.5 | 400.5 ± 2.5** | 0.08 |
| Ketoconazole | 0.4 ± 0.2 | 1.0 ± 0.3* | 0.4 | 0.3 ± 0.4 | 0.9 ± 1.1 | 0.3 |
| Quinidine | 116.4 ± 2.6 | 4.8 ± 1.3** | 24.3 | 263.2 ± 5.2 | 28.3 ± 2.1** | 9.3 |
| Reserpine | 1.0 ± 1.5 | 7.2 ± 1.4* | 0.1 | 121.8 ± 1.6 | 266.2 ± 2.8 | 0.5 |
| Tacrolimus | 6.3 ± 1.3 | 10.7 ± 1.5 | 0.6 | 9.0 ± 1.2 | 18.1 ± 1.8 | 0.5 |
| Measured Bindinga | Calculated Bindingb | |||||||
|---|---|---|---|---|---|---|---|---|
| fumic | S.D. | fuhep | S.D. | Ratio (mic/hep) | fumic | fuhep | Ratio (mic/hep) | |
| Cyclosporin A | 0.02 | 0.01 | 0.02 | 0.01 | 1.1 | 0.32 | 0.27 | 1.2 |
| Elacridar | 0.005 | 0.002 | 0.01** | 0.01 | 0.4 | 0.28 | 0.24 | 1.2 |
| Ketoconazole | 0.33 | 0.06 | 0.47 | 0.09 | 0.7 | 0.84 | 0.81 | 1.0 |
| Quinidine | 0.83 | 0.05 | 0.91 | 0.02 | 0.9 | 0.81 | 0.77 | 1.0 |
| Reserpine | 0.17 | 0.02 | 0.19 | 0.02 | 0.9 | 0.50 | 0.45 | 1.1 |
| Tacrolimus | 0.17 | 0.02 | 0.18 | 0.03 | 0.9 | 0.84 | 0.81 | 1.0 |
| Midazolam | 0.30 | 0.02 | 0.36 | 0.04 | 0.8 | 0.16 | 0.13 | 1.2 |
| Loperamide | 0.74 | 0.01 | 0.80 | 0.01 | 0.9 | 0.54 | 0.48 | 1.1 |
Mean ± S.E. listed, n = 3, for elacridar n = 4. The experiment was performed on three separate occasions. IC50 values are based on total concentration. * P < 0.05, ** P < 0.01, statistically significant difference between values in cryopreserved hepatocytes and microsomes.
Hep, cryopreserved hepatocyte; Mic, microsome.
↵a The fuinc in microsome and hepatocyte incubations was measured according to Mateus et al., 2013.
↵b The fuinc in microsome and hepatocyte incubations was calculated according to eq. 1 and eq. 2.