Open AccessCoffee inhibition of CYP 3A4 in vitro was not translated to a grapefruit‐like pharmacokinetic interaction clinically
Author(s) -
Dresser George K.,
Urquhart Brad L.,
Proniuk Julianne,
Tieu Alvin,
Freeman David J.,
Arnold John Malcolm,
Bailey David G.
Publication year - 2017
Publication title -
pharmacology research and perspectives
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.975
H-Index - 27
ISSN - 2052-1707
DOI - 10.1002/prp2.346
Subject(s) - felodipine , grapefruit juice , cmax , pharmacology , chemistry , bioavailability , pharmacokinetics , cyp3a4 , crossover study , in vitro , drug interaction , oral administration , metabolism , medicine , biochemistry , cytochrome p450 , placebo , alternative medicine , pathology , blood pressure
Grapefruit can augment oral medication bioavailability through irreversible (mechanism‐based) inhibition of intestinal CYP 3A4. 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 CYP 3A4 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 CYP 3A4 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 AUC 0–8 (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 AUC 0–8 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 CYP 3A4 inhibition, the coffees did not cause a clinical pharmacokinetic interaction possibly from insufficient amount of inhibitor(s) in coffee reaching intestinal CYP 3A4 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.