Variable Plasma/Liver and Tissue Esterase Hydrolysis of Simvastatin in Healthy Volunteers after a Single Oral Dose

Objective To identify groups of subjects who showed a high or low metabolic yield of the active metabolite simvastatin-β-hydroxy acid after oral administration of simvastatin 80mg. Study Design and Participants Plasma concentration and area under the concentration-time curve until the last measured concentration (AUC t ) data of simvastatin and its active metabolite simvastatin-β-hydroxy acid were obtained from a randomised, crossover bioequivalence study in 36 subjects [18 females, 18 males, of whom 34 (18/16) were evaluable]. Methods Participants received a single 80mg oral dose of two different formulations of simvastatin (formulations I and II). Plasma simvastatin and simvastatinβ-hydroxy acid concentrations were determined according to validated methods involving gas chromatography-mass spectrometry. Results A subject-dependent yield of the active metabolite simvastatin-β-hydroxy acid was demonstrated, which was independent of the formulation. The variation in plasma/liver hydrolysis resulted in a fan-shaped distribution of datapoints when the simvastatin AUCt was plotted versus that of the hydroxy acid etabolite. Subgroups could be distinguished in the fan of datapoints, each showing a different regression line and a different Y-intercept (AUC t for simvastatin-β-hydroxy acid). It was possible to discriminate between simvastatin hydrolysis by plasma/liver or tissue esterase activity. When only plasma/liver esterase activity is responsible for the hydrolysis of simvastatin, then with the AUC t for simvastatin approaching zero (limX→0), the AUC t for the metabolite must also approach zero (limY→0), and the 95% confidence interval of the Y-intercept must contain the zero. This situation existed in three subgroups of subjects (one with formulation I and two with formulation II), showing pure plasma and hepatic hydrolysis. In four other subgroups (two with formulation I and two with formulation II) there was a Y-intercept not containing the zero in its 95% confidence interval, indicating additional tissue esterase hydrolysis, presumably in the gastrointestinal tract. When this is the case, both parent drug and intestinally-formed metabolite are absorbed, resulting in a measurable AUC t of the metabolite when the AUC t of simvastatin equals zero. With combined AUC t data for formulations I and II, four groups can be distinguished, two of them showing plasma and hepatic carboxyesterase activity, while two groups show additional tissue esterase activity. Conclusion This study showed clearly that 10 of 34 subjects had a high yield of active metabolite, independent of the formulation. In contrast, six subjects showed an extremely low metabolite yield. A low-to-intermediate yield of active metabolite was formed in 18 subjects. As a correlation between the plasma concentration of simvastatin-β-hydroxy acid and HMG-CoA inhibitory activity has been demonstrated, the variation in plasma concentration and AUC t of this active metabolite indicates a probable variation in inhibitory activity and thus in clinical effect.