Bioequivalence & Bioavailability

Atorvastatin is a lipid-lowering agent, approved for treatment once daily at 10-80 mg doses in adults and at 10-20 mg doses in children aged 10 years or older [15]. Following oral administration, atorvastatin is rapidly absorbed, and maximum plasma concentrations are achieved within 1 to 2 hours. Atorvastatin is extensively metabolized by cytochrome P450 3A4 to active metabolites: orthoand parahydroxyatorvastatin. Approximately 70% of the circulating inhibitory activity for HMG-CoA reductase is attributed to these active metabolites [15]. In vitro inhibition of HMG-CoA reductase by orthoand para-hydroxylated metabolites is equivalent to that of atorvastatin. Ortho-hydroxyatorvastatin is the predominant active metabolite in systemic circulation [12,18]. In a single-dose study of 2.5 to 120 mg doses [16] and in multiple-dose studies of 2.5 to 80 mg dose [15], the plasma pharmacokinetics (AUC and Cmax) of atorvastatin equivalents, measured as all compounds capable of inhibiting HMG-CoA reductase, showed nonlinear increases. However, in a multiple-dose study [25], a greater than dose-proportional increase was observed only in the Cmax but not in the AUC of either atorvastatin or its active metabolites. In this multiple-dose study, atorvastatin concentrations were assayed by a gas chromatography/mass spectrometry (GC/MS) method. The difference between the atorvastatin-equivalent concentration and atorvastatin concentration represented the sum of the concentrations of active metabolites.