Article Figures & Data
Figures
- Fig. 1.
Phase I metabolism of tamoxifen. P450s metabolize tamoxifen through the “major” (N-demethylation followed by 4-hydroxylation) or “minor” (4-hydroxylation followed by N-demethylation) pathway, so denoted due to the relative abundance of each metabolite in plasma samples (Stearns et al., 2003; Madlensky et al., 2011). Conversion of NDT to endoxifen is catalyzed exclusively by CYP2D6 (Desta et al., 2004).
- Fig. 2.
CYP2D6 converts NDT to endoxifen in hCYP2D6 mice. (A) Kinetic analysis of endoxifen formation in hCYP2D6 MLMs (pooled from four animals). Data represent combined means ± S.D. of 10 technical replicates carried out on four separate occasions. (B) Endoxifen formation in MLMs and HLMs. MLMs were pooled from three (Cyp2dKO, WT) or four (hCYP2D6) individual animals. HLMs were individual (13 donors) or pooled (150 donors). Data represent means ± S.D. of duplicate incubations and are representative of an experiment carried out on two separate occasions. WT, wild type.
- Fig. 3.
Conversion of NDT to endoxifen in hCYP2D6 MLMs is inhibited by ADs. Paroxetine was preincubated with MLMs before addition of NDT, as described in the Materials and Methods. All other compounds were coincubated with NDT. Data represent means of duplicate incubations and are representative of an experiment carried out on two separate occasions.
- Fig. 4.
Paroxetine inhibits conversion of NDT (A) to endoxifen (B) in hCYP2D6 in vivo. (C) Animals were dosed with paroxetine (8 mg/kg, n = 6) or vehicle (n = 6) and then, 1 hour subsequently, all were dosed with NDT (10 mg/kg). Data shown are means ± S.E.M.
Tables
- TABLE 1
Spearman’s rank correlation of conversion of NDT to endoxifen with P450 probe substrate metabolism in a panel of 13 HLMs
Spearman’s rank correlation coefficient of NDT hydroxylation with metabolism of P450 probe substrates is shown. Probe substrate values were provided by the vendor.
Enzyme Probe Substrate Activity SRCC with NDT Hydroxylation P Value 1A2 Phenacetin O-deethylation −0.289 0.360 2A6 Coumarin 7-hydroxylation 0.161 0.600 2B6 S-mephenytoin N-demethylation 0.572 0.045 2C8 Paclitaxel 6α-hydroxylation 0.380 0.186 2C9 Diclofenac 4′-hydroxylation 0.526 0.076 2C19 S-mephenytoin 4′-hydroxylation −0.220 0.444 2D6 Bufuralol 1′-hydroxylation 0.698 0.010 2E1 Chlorzoxazone 6-hydroxylation 0.311 0.281 3A4 Testosterone 6β-hydroxylation −0.005 0.993 4A11 Lauric acid 12-hydroxylation −0.290 0.316 SRCC, Spearman’s rank correlation coefficient.
- TABLE 2
PK parameters of endoxifen in hCYP2D6 mice
Parameters (means ± S.D.) are shown for vehicle (n = 6) and paroxetine (n = 6) pretreated groups.
Group t1/2 Cmax AUCall h ng/ml h⋅ng/ml Vehicle 14.3 ± 4.7 132 ± 46 3508 ± 797 Paroxetine 13.8 ± 3.1 104 ± 12 2525 ± 321* P value 0.416 0.094 0.009 t1/2, half-life. *P <0.05.
Data Supplement
Files in this Data Supplement:
- Supplemental Figures -
Supplemental Figure 1 - Spearman's rank correlation of NDT hydroxylation with CYP2B6 and and CYP2D6 probe activities
Supplemental Figure 2 - E0771 cell proliferation is independent of oestradiol in vitro
Supplemental References
- Supplemental Figures -
