Apparent Km and Vmax values as well as intrinsic clearances (CLint) for the formation of atorvastatin and atorvastatin lactone metabolites by human liver microsomes, isolated cDNA-expressed CYP3A4, and 2C8 enzymes
| Sample | Atorvastatin | Atorvastatin Lactone | ||
|---|---|---|---|---|
| para-Hydroxy | ortho-Hydroxy | para-Hydroxy | ortho-Hydroxy | |
| Human liver microsomes | ||||
| K m (μmol · l−1) | ||||
| HLF1 | 38.9 | 40.9 | 1.2 | 1.3 |
| HLF2 | 27.0 | 28.1 | 0.8 | 1.5 |
| HLM1 | 39.6 | 36.1 | 2.6 | 2.1 |
| HLM2 | 33.5 | 26.9 | 2.7 | 1.6 |
| Mean ± S.D. | 34.8 ± 5.8 | 33.0 ± 6.7 | 1.8 ± 1.0 | 1.6 ± 0.3 |
| V max[pmol · min−1 · mg−1(pmol · min−1 · pmol CYP−1)] | ||||
| HLF1 | 337 (1.2) | 482 (1.7) | 2801 (9.9) | 1165 (4.1) |
| HLF2 | 2907 (5.1) | 3774 (6.6) | 6451 (11.3) | 3436 (6.0) |
| HLM1 | 542 (1.4) | 625 (1.6) | 2851 (7.4) | 752 (2.0) |
| HLM2 | 406 (1.3) | 529 (1.7) | 813 (2.7) | 234 (0.8) |
| Mean ± S.D. | 1048 ± 1242 | 1353 ± 1615 | 3229 ± 2349 | 1397 ± 1412 |
| (2.3 ± 1.9) | (2.9 ± 2.5) | (9.6 ± 2.0) | (3.2 ± 2.3) | |
| CLint(μl · min−1 · mg−1) | 35.5 ± 48.1 | 45.8 ± 59.1 | 2949 ± 3511 | 923 ± 965 |
| CYP3A4 | ||||
| K m(μmol · l−1; mean ± S.D., n = 3) | 25.6 ± 5.0 | 29.7 ± 9.4 | 1.4 ± 0.2 | 3.9 ± 0.2 |
| V max[pmol · min−1 · mg−1 | 5463 ± 169 | 5376 ± 409 | 14312 ± 348 | 4235 ± 205 |
| (pmol · min−1 · pmolCYP−1); mean ± S.D.; n = 3] | (29.8 ± 5.1) | (29.3 ± 5.3) | (70.1 ± 1.7) | (20.7 ± 1.6) |
| CLint(μl · min−1 · mg−1) | 219 ± 33.1 | 184 ± 26.3 | 10795 ± 1341 | 1092 ± 42 |
| CYP2C8 | ||||
| K m(μmol · L−1; mean ±S.D.; n = 3) | 35.9 ± 4.1 | <LLOQ | <LLOQ | <LLOQ |
| V max[pmol · min−1 · mg−1 | 161.0 ± 11.5 | <LLOQ | <LLOQ | <LLOQ |
| (pmol · min−1 · pmol CYP−1); mean ± S.D.; n = 3] | (0.29 ± 0.02) | |||
| CLint(μl · min−1 · mg−1) | 4.5 ± 0.2 | |||
Data are presented as mean ± S.D. Liver microsomes were prepared from four patients [2 female (HLF) and 2 male (HLM)]. ApparentKm and Vmax were calculated after linearization according to Hanes-Woolf using Sigma-Plot software. CLint, intrinsic clearance of metabolite formation (Vmax/Km); <LLOQ, concentration below lower limit of quantitation.