Objective: To identify the differences in esterase hydrolysis of lovastatin between male and female volunteers.
Study design and participants: Data for plasma concentration and area under the concentration-time curve until the last measured concentration (AUCt) of lovastatin and its active metabolite lovastatin-β-hydroxy acid (mevinolinic acid) were obtained from a randomised, crossover bioequivalence study in 36 subjects (18 females and 18 males).
Methods: Participants received a single 80mg oral dose of two different formulations of lovastatin (formulations I and II). Plasma lovastatin and lovastatin-β-hydroxy acid concentrations were determined according to validated methods involving gas chromatography-mass spectrometry.
Results: The group of female volunteers showed a higher yield of the active metabolite lovastatin-β-hydroxy acid than the group of males (p < 0.002). This difference was not related to the bodyweight of the two groups. In both male and female groups, a subject-dependent yield of lovastatin-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 AUCt of lovastatin was plotted against that of the hydroxy acid metabolite. In the fan of datapoints, subgroups could be distinguished, each showing a different regression line and with a different y-intercept (AUCt of lovastatin-β-hydroxy acid). It was possible to discriminate between hydrolysis of lovastatin by plasma/liver or tissue esterase activity. The three subgroups of subjects (males/females) showing a different but high yield of lovastatin-β-hydroxy acid can be explained by variable hydrolysis by plasma and hepatic microsomal and cytosolic carboxyesterase activity.
Conclusion: This study showed clearly that in addition to subject-dependent hydrolysis of lovastatin to the active metabolite, males tend to hydrolyse less than females. Therefore, the dosage of lovastatin should be individualised with reference to plasma concentration or clinical effect.
Simvastatin Lovastatin Esterase Activity Liver Esterase Primary Active Metabolite
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