TABLE 3.
Pharmacokinetic properties of NVR 3-778 in PHHs cultured in HCM spiked with or without plasma proteins
| Condition | Mean value ± SEM (fold change)a |
|||||
|---|---|---|---|---|---|---|
| CLint,app (μl/min/106 cells) | CLint,u (μl/min/106 cells) | AUClast (ng · h/ml) | Cavg (μM) | Kp | Drug concn in liver/drug concn in mediumb | |
| no BSA, no hA1GP | 89.49 ± 5.33 | 122.75 ± 7.32 | 8,248 | 0.26 | 175.89 ± 14.90 | 47.12 ± 0.61 |
| 4.3% BSA + 0.07% hA1GP | 15.77 ± 0.45 (5.7) | 162.56 ± 4.61 (1.3) | 24,749 (3.0) | 0.79 (3.0) | 30.96 ± 2.02 (5.7) | 8.29 ± 0.20 (5.7) |
| 8% BSA + 0.07% hA1GP | 10.77 ± 0.14 (8.3) | 168.33 ± 2.22 (1.4) | 26,146 (3.2) | 0.84 (3.2) | 19.26 ± 1.58 (9.1) | 5.16 ± 0.05 (9.1) |
After 5 days of culturing, mock-infected PHHs were incubated with 1 μM NVR 3-778 for 4 days. Cells and supernatant were collected after 1, 24, 48, and 72 h to quantify turnover of the parent drug. Fold changes were calculated based on pharmacokinetic results obtained in PHHs cultured in HCM without BSA and hA1GP. CLint,app, intrinsic apparent clearance; CLint,u, unbound intrinsic clearance; AUClast, area under the concentration-time curve from time zero to the last measurable concentration; Cavg, average concentration; Kp, partition coefficient. Data represent mean values of three replicates ± SEM.
Ratio of the predicted concentration of NVR 3-778 per gram of liver tissue (nanograms/gram of liver tissue) to the concentration of NVR 3-778 in the medium (nanograms/milliliter), normalized for hepatocellularity.