A reply:

Abstract

In their letter to the editor, Josefsson & Ahlner correctly admit that grapefruit juice has no appreciable effect on the pharmacokinetics and pharmacodynamics of amlodipine. However, they argue that in their paper [1], Cmax as well as AUC were significantly (P < 0.05) higher when 5 mg amlodipine was administered with 250 ml of grapefruit juice compared with when administered with water. They claim that variability in the pharmacokinetics of amlodipine rather than variability due to analytical methods underlie the differences in the conclusions from their paper compared with the results from our study [2], although they did not indicate the confidence intervals of the ratios of their Cmax and AUC. In addition, Josefsson & Ahlner claim that whereas they showed data from all their subjects, we excluded one half of our subjects and implicitly skewed our results. While pharmacokinetic variations due to biological factors are feasible, the magnitude of the mean absolute bioavailability for amlodipine reported in our study is in agreement with data reported independently by Abernethy et al.[3], as well as data on file from a study in mildly hypertensive patients. With an absolute bioavailability > 80%, bioavailability enhancement as described for calcium channel blockers with a high first-pass metabolism when grapefruit juice is concurrently administered is unlikely to be significant with amlodipine, even if one assumes complete absorption. There is a correlation between blood pressure fall and plasma concentrations of calcium channel blockers [4–6], including amlodipine [3]. In studies with felodipine and nisoldipine, significant changes in exposure following concurrent administration of grapefruit juice were accompanied by changes in haemodynamics [7, 8]. The absence of any change in blood pressure or heart rate in their study is therefore consistent with the absence of any meaningful changes in blood concentrations of amlodipine. The assertion that we excluded subjects in our analysis is a complete misrepresentation of our paper. Pharmacokinetic and pharmacodynamic data from all 20 subjects were used in the analyses of both the oral and intravenous arms of the data on unresolved amlodipine. Plasma samples collected during our study were assayed for unresolved amlodipine prior to enantiomer assays being run. In a few subjects, the volume of plasma was inadequate at all time points for the enantiomer assays. We correctly identified all such data in our manuscript. We believe that the conclusions from our study have not been compromised because of the missing enantiomer data, recognizing the consistency of the data shown. There were also substantial differences between the conditions and design of our study and the study reported by Josefsson & Ahlner. We used a larger sample size of 20 subjects compared with their 12 subjects. We also used a higher dose of amlodipine (10 vs 5 mg), to ensure a more appropriate characterization of plasma concentrations over a longer interval. In our study, grapefruit juice was administered with amlodipine on the day of dosing and repeated daily with breakfast for the 9 days during which blood samples were obtained for pharmacokinetics. This profile more clearly mimics real life situations for subjects who routinely drink grapefruit juice with breakfast when medications are commonly consumed. In addition, the conditions of our study would more readily demonstrate any potential interaction, recognizing that grapefruit juice was on board continuously. Finally, we studied both oral and intravenous amlodipine to more appropriately define its pharmacokinetics under the conditions of our study. The results with both formulations were consistent for both unresolved amlodipine and the enantiomers. In conclusion, while it may be argued that normal biological variability could influence the pharmacokinetic data shown in these studies, it is unfortunate that Josefsson & Ahlner misrepresented our data in their letter. We agree with the conclusion in their paper that grapefruit juice does not alter the pharmacokinetics and pharmacodynamics of amlodipine.