Cerivastatin 7 (Figure 7), another entirely synthetic statin, is one of the most potent inhibitors of HMG-CoA reductase (Ki = 1.3 pM) identified.66 Cerivastatin contains a unique penta-substituted pyridine core, retains the unsaturated E-heptenoic acid side chain with the identical (3R, 5S) chirality found in fluvastatin, and is about 100-fold more potent than lovastatin. Cerivastatin was orally active in animal models in the low mgkg— 1 range. For example, in normal chow-fed dogs, oral cerivastatin at 0.01-0.1 mg kg— 1 day— 1 dose-dependently reduced LDLc plasma levels after 18 days, and this reduction reached a maximum of 75% with the 0.1 mgkg — 1 day— 1 dose. Similarly, low oral daily doses of 0.1 mgkg — 1 of cerivastatin reduced plasma LDLc and the progression of atherosclerosis in rabbit models after 9 weeks of dosing.
The lower doses of cerivastatin administered in animal studies were also effective in humans where, at daily doses of 0.025-0.4 mg, cerivastatin reduced LDLc levels dose-dependently and by greater than 50% using the 0.4 mg daily dose. Cerivastatin has a much higher overall oral bioavailability (~ 60%) than other statins and is metabolized in humans by both CYP3A4 and CYP2C8. Like many other statins, it is highly protein-bound (>95%), in spite of its fairly low ClogP (1.5). Cerivastatin 7 was first approved for human use in the UK in 1997. It was voluntarily withdrawn in 2001 after higher incidences of severe myopathy and renal failure were observed in cerivastatin-treated patients, particularly in patients co-treated with gemfibrozil.
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