Grapefruit juice has minimal effects on plasma concentrations of lovastatin-derived 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors

Objective: To evaluate the effect of regular-strength grapefruit juice, a c ytochrome P4503A4 (CYP3A4) inhibitor, on the pharmacokinetics of a commonly prescribed regimen of oral lovastatin. Methods: In a randomized crossover study, 16 healthy subjects received a si ngle 40 mg dose of lovastatin in the evening after each consumed an 8-ounce glass of regular-strength grapefruit juice or water with breakfast for 3 c onsecutive days. The effect of the same grapefruit juice and water regimen on the pharmacokinetics of midazolam (2 mg oral dose given 1 hour after the third day of grapefruit juice and water) was used as a positive control in the same subjects, Plasma concentrations of 3-hydroxy-3-methylglutaryl coe nzyme A (HMG-CoA) reductase inhibitors were determined by an enzyme inhibit ion assay, and concentrations of lovastatin, lovastatin acid, and midazolam were determined by liquid chromatography-tandem mass spectrometry. Results: The area under the plasma concentration-time profiles (AUC) and ma ximum plasma concentrations (C-max) of HMG-CoA reductase inhibitors increas ed slightly (similar to 30% for each) after consumption of grapefruit juice . Similar effects on AUC and C-max (similar to 40% increase for each) were noted after analysis of samples of hydrolyzed plasma (which converts inacti ve lactones to active hydroxy acid species). The AUC and C-max values for l ovastatin approximately doubled in the presence of grapefruit juice, wherea s the same parameters for lovastatin acid increased 1.6-fold. Grapefruit ju ice caused the AUC for midazolam to increase by a factor of similar to 2,4. Conclusions: Daily consumption of a glass of regular-strength grapefruit ju ice has a minimal effect on plasma concentrations of HMG-CoA reductase inhi bitors (similar to 30% to 40% increase) after a 40 mg evening dose of lovas tatin.