Table 1.
Plasma and media unbound fractions for the studied retinoids, in vitro EC50,u values, and predicted magnitude of in vivo change in CYP2D6 based on clinical 13cisRA, atRA, and 4‐oxo‐13cisRA exposures
| End point | Precipitant | |||
|---|---|---|---|---|
| 13cisRA | atRA | 4‐oxo‐13cisRA | Combined parent and metabolitesa | |
| f u,plasma b | 0.0004 (0.0001) | 0.0002 (5 × 10−5) | 0.012 (0.004) | |
| f u,media b | 0.011 (0) | 0.027 (0.008) | 0.121 (0.013) | |
| Cavg c (μM) | 0.69 | 0.01 | 5.4 | |
| Donor 1 d | ||||
| Emin | 0.63 (0.57–0.68) | 0.64 (0.58–0.70) | 0.63 (0.58–0.69) | |
| EC50,u (nM) | 0.18 (0.09–0.44) | 0.37 (0.16–0.81) | 3.8 (1.2–8.5) | |
| Predicted % CYP2D6 remaining | 0.78 | 1.0 | 0.65 | 0.65 |
| Donor 3 e | ||||
| Emin | 0.05 | 0.07 | 0.05 | |
| EC50,u (nM) | 0.91 | 1.3 | 17 | |
| Predicted % CYP2D6 remaining | 0.78 | 1.0 | 0.24 | 0.23 |
Donor 2 was excluded from quantitative predictions due to the wide confidence intervals of the determined EC50 values of retinoids on CYP2D6 mRNA in this donor (Figure 1 ).
atRA, all‐trans‐RA; Cavg, average concentration; CYP, cytochrome P450; EC50,u, unbound half‐maximal effective concentration; Emin, minimum concentration; fu,plasma, fraction unbound in plasma; fu,media, fraction unbound in media; NA, not applicable; RA, retinoic acid.
aThe combined effect of 13cisRA and its metabolites on CYP2D6 expression in vivo was predicted using Eq. (2). bBinding experiments were conducted in triplicate and data are presented as mean (SD). cCavg following administration of 20 mg b.i.d. 13cisRA reported in Amory et al.17 dThe concentration‐dependent effects of retinoids in donor 1 hepatocytes are presented as mean (90% confidence interval). eThe concentration‐dependent effects of retinoids in donor 3 hepatocytes were assessed in three replicate experiments, and the median value from the three experiments is reported.