Table 1

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

SampleAtorvastatinAtorvastatin Lactone
para-Hydroxyortho-Hydroxypara-Hydroxyortho-Hydroxy
Human liver microsomes
K m (μmol · l−1)
  HLF138.940.91.21.3
  HLF227.028.10.81.5
  HLM139.636.12.62.1
  HLM233.526.92.71.6
  Mean ± S.D.34.8  ± 5.833.0  ± 6.7 1.8  ± 1.0 1.6  ± 0.3
V max[pmol · min−1 · mg−1(pmol · min−1 · pmol CYP−1)]
  HLF1337 (1.2)482 (1.7)2801 (9.9)1165 (4.1)
  HLF22907 (5.1)3774 (6.6)6451 (11.3)3436 (6.0)
  HLM1542 (1.4)625 (1.6)2851 (7.4)752 (2.0)
  HLM2406 (1.3)529 (1.7)813 (2.7)234 (0.8)
  Mean ± S.D.1048  ± 12421353  ± 16153229  ± 23491397  ± 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  ± 48.145.8  ± 59.12949  ± 3511923  ± 965
CYP3A4
K m(μmol · l−1; mean ± S.D., n = 3)25.6  ± 5.029.7  ± 9.41.4  ± 0.23.9  ± 0.2
V max[pmol · min−1 · mg−1 5463  ± 1695376  ± 40914312  ± 3484235  ± 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  ± 33.1184  ± 26.310795  ± 13411092  ± 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.