Inhibition of atorvastatin and atorvastatin lactone glucuronidation by gemfibrozil, fenofibrate, and fenofibric acid
HLMs (0.5 mg/ml) were pretreated with alamethicin (50 μg/mg of protein) and incubated with increasing concentrations of fibrates (0.03–1000 μM) in Tris-HCl buffer to determine IC50 values. Values represent means ± S.E.M. from three experiments.
Pathwaya | IC50 | ||||
|---|---|---|---|---|---|
| Gemfibrozil | Fenofibrate | Fenofibric Acid | |||
| μM | |||||
| G1 formationb | Increased | Increased | Increased | ||
| 1.6-fold | 6.7-fold | 9.5-fold | |||
| Lactonization | 346 ± 7 | 320 ± 6 | 291 ± 15 | ||
| G3 formation | NA | ∼1000c | ∼1000c | ||
NA, not applicable.
↵ a G1 is a minor atorvastatin ether glucuronide. Lactonization is the major glucuronidation pathway for atorvastatin, mediated via acyl glucuronide (G2) formation, calculated from summation of G2 and atorvastatin lactone as products. G3 is the atorvastatin lactone glucuronide.
↵ b G1 formation was not inhibited by fibrates but generally increased with increasing fibrate concentration.
↵ c Mean inhibition as 45 and 49.9% in the presence of 1000 μM fenofibrate and fenofibric acid, respectively.