Table 2

Inhibition of the metabolism of atorvastatin (30 μM) and atorvastatin lactone (2 μM) by CYP3A substrates and/or inhibitors

InhibitorAtorvastatinAtorvastatin Lactone
para-Hydroxyortho-Hydroxypara-Hydroxyortho-Hydroxy
Fluconazole9.1  ± 2.87.5  ± 3.612.8  ± 3.718.5  ± 2.6
Saquinavir0.6  ± 0.40.6  ± 0.50.5  ± 0.40.4  ± 0.2
Itraconazole0.05  ± 0.030.04  ± 0.010.03  ± 0.010.03  ± 0.01
Atorvastatin90.0  ± 28.5>90
Atorvastatin lactone0.9  ± 0.40.9  ± 0.3

Apparent inhibition constants (Ki) are given as mean ± S.D. (n = 4 different preparations of human liver microsomes). For the inhibition studies, atorvastatin and atorvastatin lactone concentrations close to theirKm (Table 1) were chosen. ApparentKi values were estimated based on half-maximal inhibition concentrations (IC50), which were determined separately for para- and ortho-hydroxy metabolite formation, and the apparent Km values shown in Table1 using the Cheng-Prusoff equation (Cheng and Prusoff, 1973).