Coffee inhibition of CYP3A4 in vitro was not translated to a grapefruit-like pharmacokinetic interaction clinically.

Grapefruit can augment oral medication bioavailability through irreversible (mechanism-based) inhibition of intestinal CYP3A4. Supplementary data from our recent coffee-drug interaction clinical study showed some subjects had higher area under the plasma drug concentration - time curve (AUC) and plasma peak drug concentration (Cmax) of the CYP3A4 probe felodipine compared to aqueous control. It was hypothesized that coffee might interact like grapefruit in responsive individuals. Beans from six geographical locations were consistently brewed into coffee that was separated chromatographically to a methanolic fraction for in vitro inhibition testing of CYP3A4 metabolism of felodipine at 1% coffee strength. The effect of simultaneous incubation and 10-min preincubation with coffee fractions determined whether coffee had direct and mechanism-based inhibitory activity. A subsequent five-way randomized balanced controlled crossover clinical study evaluated the clinical pharmacokinetic interaction with single-dose felodipine. Grapefruit juice, water, or three of the in vitro tested coffees were ingested at 300 mL alone 1 h before and then with felodipine. In vitro, all six coffees decreased felodipine metabolism for both simultaneous and preincubation exposure compared to corresponding control. Five coffees demonstrated mechanism-based inhibition. Grapefruit increased felodipine AUC0-8 (25 vs. 13 ng.h/mL, P < 0.001) and Cmax (5.8 vs. 2.7 ng/mL, P < 0.001) and decreased dehydrofelodipine/felodipine AUC0-8 ratio (0.84 vs. 1.29, P < 0.001), while the three coffees caused no change in these parameters compared to water. Despite high in vitro potency of CYP3A4 inhibition, the coffees did not cause a clinical pharmacokinetic interaction possibly from insufficient amount of inhibitor(s) in coffee reaching intestinal CYP3A4 during the absorption phase of felodipine. The results of this study highlight the need for follow-up clinical testing when in vitro results indicate the possibility of an interaction.

Coffee-Antihypertensive Drug Interaction: A Hemodynamic and Pharmacokinetic Study With Felodipine.

OBJECTIVES: A period of abstinence from coffee to permit caffeine elimination appears to enable increased blood pressure on subsequent exposure. We hypothesized that this would offset the antihypertensive effect of the dihydropyridine calcium channel blocker felodipine. METHODS: A randomized, single-dose, crossover study assessed hemodynamic and pharmacokinetic effects following 2 days without coffee and caffeine-containing foods. Consistently brewed black coffee (2×300ml), felodipine maximum recommended dose (10mg), and coffee plus felodipine were tested in middle-aged normotensive subjects. RESULTS: Pretreatment plasma caffeine concentrations were unquantifiable. After coffee, blood pressure changes (mm Hg) averaged over study hours 1-4 were increased for brachial systolic (7.6, P < 0.001) and diastolic (4.9, P < 0.001) and aortic systolic (7.4, P < 0.001), pulse (3.0, P < 0.05) and augmentation (1.4, P < 0.05) relative to baseline. After coffee plus felodipine, they were higher for brachial systolic (4.0, P < 0.05) and diastolic (3.9, P < 0.001) and aortic systolic (4.6, P < 0.05) compared to felodipine alone. The pressor effects of coffee and its modulation by felodipine were variable among individuals. Coffee containing caffeine (127mg) caused maximum pressor effect. Caffeine and felodipine pharmacokinetics were similar for coffee and felodipine given alone or in combination indicating an interaction having a pharmacodynamic basis. Plasma felodipine concentration-diastolic blood pressure reduction relationship shifted with coffee such that doubling the felodipine concentration would eliminate the pressor effect. However, this may increase the risk of adverse drug events particularly during the timeframe without coffee. CONCLUSION: Intermittent coffee ingestion might complicate hypertension diagnosis and management for many individuals.