Measured amiodarone N-deethylase activities by recombinant CYP isoforms and in human liver microsomes and predicted amiodarone N-deethylase activities by each CYP isoform using RAF
| Enzyme | Substrate Concentration | CYPx | Sum | Measured Activity | ||||
|---|---|---|---|---|---|---|---|---|
| CYP1A2 | CYP2C8 | CYP2C19 | CYP2D6 | CYP3A4 | ||||
| μM | pmol/min/nmol CYP | |||||||
| Recombinant CYP | ||||||||
| V rec-CYPx | 5 | 278 | 1023 | 72 | 409 | 1343 | ||
| 10 | 1173 | 1195 | 498 | 631 | 1993 | |||
| 20 | 1724 | 1362 | 794 | 1185 | 3999 | |||
| 50 | 2457 | 1877 | 933 | 1613 | 9088 | |||
| 100 | 3595 | 2219 | 1038 | 1815 | 15329 | |||
| Human liver microsomes | ||||||||
| HLG 1 | 5 | 0.3 (0.2)4-a | 82.7 (40.8) | 0.7 (0.3) | 14.6 (7.2) | 104.5 (51.5) | 202.8 | 182.5 |
| 10 | 1.4 (0.5) | 96.6 (34.4) | 4.9 (1.7) | 22.5 (8.0) | 155.1 (55.3) | 280.4 | 322.2 | |
| 20 | 2.1 (0.4) | 110.0 (23.3) | 7.8 (1.6) | 42.3 (8.9) | 311.1 (65.7) | 473.3 | 513.0 | |
| 50 | 3.0 (0.3) | 151.7 (16.3) | 9.1 (1.0) | 57.6 (6.2) | 707.0 (76.2) | 928.4 | 758.2 | |
| 100 | 4.3 (0.3) | 179.3 (12.4) | 10.2 (0.7) | 64.8 (4.5) | 1192.6 (82.2) | 1451.2 | 933.0 | |
| HLG 4 | 5 | 3.3 (1.6) | 98.2 (47.0) | 1.6 (0.7) | 0.5 (0.2) | 105.4 (50.4) | 209.0 | 192.8 |
| 10 | 14.1 (4.7) | 114.7 (38.7) | 10.7 (3.6) | 0.8 (0.3) | 156.5 (52.7) | 296.7 | 352.1 | |
| 20 | 20.7 (4.3) | 130.8 (27.0) | 17.0 (3.5) | 1.4 (0.3) | 313.9 (64.9) | 483.8 | 481.8 | |
| 50 | 29.5 (3.1) | 180.2 (19.1) | 20.1 (2.1) | 1.9 (0.2) | 713.4 (75.5) | 945.1 | 870.0 | |
| 100 | 43.1 (2.9) | 213.0 (14.4) | 22.3 (1.5) | 2.2 (0.1) | 1203.3 (81.1) | 1484.0 | 1101.0 | |
| HLG 6 | 5 | 5.4 (3.9) | 43.2 (30.8) | 5.8 (4.1) | 4.4 (3.1) | 81.4 (58.1) | 140.1 | 58.8 |
| 10 | 22.9 (9.5) | 50.4 (20.9) | 39.9 (16.6) | 6.8 (2.8) | 120.8 (50.2) | 240.7 | 193.6 | |
| 20 | 33.6 (8.2) | 57.5 (14.0) | 63.4 (15.5) | 12.7 (3.1) | 242.8 (59.2) | 409.5 | 439.5 | |
| 50 | 47.9 (6.2) | 79.2 (10.3) | 74.7 (9.7) | 17.3 (2.2) | 550.7 (71.5) | 769.8 | 633.8 | |
| 100 | 70.1 (5.9) | 93.6 (7.8) | 83.1 (7.0) | 19.4 (1.6) | 928.9 (77.7) | 1195.2 | 804.9 | |
| V CYPx | ||||||||
| HLG 7 | 5 | 3.5 (3.7) | 36.0 (37.8) | 1.6 (1.7) | 10.5 (11.0) | 43.6 (45.8) | 95.3 | 81.0 |
| 10 | 14.8 (9.9) | 42.1 (28.3) | 11.1 (7.4) | 16.2 (10.9) | 64.8 (43.5) | 148.9 | 98.0 | |
| 20 | 21.7 (8.8) | 47.9 (19.4) | 17.6 (7.1) | 30.5 (12.3) | 130.0 (52.5) | 247.6 | 313.8 | |
| 50 | 31.0 (6.8) | 66.1 (14.5) | 20.7 (4.6) | 41.5 (9.1) | 295.4 (65.0) | 454.6 | 473.6 | |
| 100 | 45.3 (6.6) | 78.1 (11.3) | 23.0 (3.3) | 46.6 (6.7) | 498.2 (72.1) | 691.3 | 706.0 | |
| HLG 10 | 5 | 5.4 (2.2) | 68.1 (28.3) | 1.7 (0.7) | 1.6 (0.7) | 164.2 (68.1) | 241.1 | 149.1 |
| 10 | 22.8 (6.3) | 79.6 (22.1) | 11.8 (3.3) | 2.5 (0.7) | 243.7 (67.6) | 360.4 | 457.7 | |
| 20 | 33.4 (5.3) | 90.7 (14.2) | 18.7 (2.9) | 4.7 (0.7) | 489.1 (76.8) | 636.6 | 821.4 | |
| 50 | 47.7 (3.6) | 125.0 (9.5) | 22.0 (1.7) | 6.5 (0.5) | 1111.5 (84.7) | 1312.6 | 1646.0 | |
| 100 | 69.7 (3.3) | 147.8 (7.0) | 24.5 (1.2) | 7.3 (0.3) | 1874.7 (88.3) | 2124.0 | 1959.3 | |
| HLG 11 | 5 | 6.7 (7.0) | 57.6 (60.0) | 0.5 (0.5) | 5.7 (6.0) | 25.4 (26.5) | 95.9 | 63.0 |
| 10 | 28.3 (19.4) | 67.3 (46.2) | 3.6 (2.5) | 8.8 (6.1) | 37.7 (25.9) | 145.6 | 91.3 | |
| 20 | 41.5 (19.2) | 76.7 (35.5) | 5.7 (2.6) | 16.6 (7.7) | 75.6 (35.0) | 216.1 | 233.8 | |
| 50 | 59.2 (16.2) | 105.7 (28.9) | 6.7 (1.8) | 22.6 (6.2) | 171.8 (46.9) | 366.0 | 410.4 | |
| 100 | 86.6 (16.2) | 124.9 (23.4) | 7.5 (1.4) | 25.4 (4.8) | 289.7 (54.2) | 534.2 | 492.0 | |
↵4-a Numbers in parentheses indicate the percentage of contribution of the isoform to amiodaroneN-deethylase activity.