How Grapefruit Juice Raised the AUC of Felodipine | Enzyme Inhibition (Drug Interactions 11.1)

How does an inhibitor of a drug-metabolizing enzyme change the plasma concentration of another drug? Lesson 11.1 of our drug interactions module covers four parts: reversible inhibition, time-dependent inhibition, the site of inhibition, and the size of the effect. The worked example is grapefruit juice with felodipine, with published data on time-dependent inhibition, inhibition in the gut wall and the AUC ratio. 0:00 Precipitant, object and inhibitor 0:48 Reversible inhibition 1:28 Time-dependent inhibition 1:55 Site of inhibition 2:56 Size of the effect 3:42 Grapefruit juice and felodipine 4:23 Time-dependent inhibition by the juice 5:27 Inhibition in the gut wall 6:14 AUC ratio and blood pressure 7:03 Summary Sources International Council for Harmonisation. M12 Drug interaction studies. ICH guideline. 2024. https://ema.europa.eu/en/documents/sc... Reynolds K, Yang X, Peters SA, et al. ICH M12 drug interaction studies: summary of the efforts to achieve global convergence. Clin Pharmacol Ther. 2025. PMID 40108838 Scotcher D, Ghosh A, Galetin A, et al. Addressing a common misconception of simple additive and cumulative drug inhibition: multiple weak inhibitors of common metabolic pathway do not pose a strong interaction risk! J Clin Pharmacol. 2026. PMID 41618569 Lin JH, Lu AY. Inhibition and induction of cytochrome P450 and the clinical implications. Clin Pharmacokinet. 1998. PMID 9839089 Zhou S, Yung Chan S, Cher Goh B, et al. Mechanism-based inhibition of cytochrome P450 3A4 by therapeutic drugs. Clin Pharmacokinet. 2005. PMID 15762770 Lown KS, Bailey DG, Fontana RJ, et al. Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression. J Clin Invest. 1997. PMID 9153299 Yim DS. Tutorial for beginners: the concept of clearance explained using the example of a vacuum cleaner. Transl Clin Pharmacol. 2017. PMID 32095451 Gorski JC, Jones DR, Haehner-Daniels BD, et al. The contribution of intestinal and hepatic CYP3A to the interaction between midazolam and clarithromycin. Clin Pharmacol Ther. 1998. PMID 9728893 Greenblatt DJ, von Moltke LL, Harmatz JS, et al. Time course of recovery of cytochrome P450 3A function after single doses of grapefruit juice. Clin Pharmacol Ther. 2003. PMID 12891222 Par Health USA. Felodipine extended-release tablets USP: DailyMed label. 2024. https://dailymed.nlm.nih.gov/dailymed... Schmiedlin-Ren P, Edwards DJ, Fitzsimmons ME, et al. Mechanisms of enhanced oral availability of CYP3A4 substrates by grapefruit constituents. Decreased enterocyte CYP3A4 concentration and mechanism-based inactivation by furanocoumarins. Drug Metab Dispos. 1997. PMID 9351897 Paine MF, Widmer WW, Hart HL, et al. A furanocoumarin-free grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juice-felodipine interaction. Am J Clin Nutr. 2006. PMID 16685052 Lundahl J, Regårdh CG, Edgar B, et al. Effects of grapefruit juice ingestion: pharmacokinetics and haemodynamics of intravenously and orally administered felodipine in healthy men. Eur J Clin Pharmacol. 1997. PMID 9174684 US Food and Drug Administration. Healthcare Professionals: FDA's Examples of Drugs that Interact with CYP Enzymes and Transporter Systems. 2026. https://www.fda.gov/drugs/drug-intera... Bailey DG, Spence JD, Munoz C, et al. Interaction of citrus juices with felodipine and nifedipine. Lancet. 1991. PMID 1671113 Illustrations adapted from Servier Medical Art (smart.servier.com), CC BY 4.0. Structures drawn with RDKit.