Grapefruit‐Drug Interactions: Can Interactions With Drugs Be Avoided?

Grapefruit is rich in flavonoids, which have been demonstrated to have a preventive influence on many chronic diseases, such as cancer and cardiovascular disease. However, since the early 1990s, the potential health benefits of grapefruit have been overshadowed by the possible risk of interactions between drugs and grapefruit and grapefruit juice. Several drugs interacting with grapefruit are known in different drug classes, such as HMG‐CoA reductase inhibitors, calcium antagonists, and immunosu‐pressives. Currently known mechanisms of interaction include the inhibition of cytochrome P450 as a major mechanism, but potential interactions with P‐glycoprotein and organic anion transporters have also been reported. This review is designed to provide a comprehensive summary of underlying mechanisms of interaction and human clinical trials performed in the area of grapefruit drug interactions and to point out possible replacements for drugs with a high potential for interactions.

[1]  E. Ernst,et al.  Cardiovascular pharmacotherapy and herbal medicines: the risk of drug interaction. , 2005, International journal of cardiology.

[2]  S. E. Rau,et al.  Grapefruit juice—terfenadine single‐dose interaction: Magnitude, mechanism, and relevance , 1997, Clinical pharmacology and therapeutics.

[3]  P. Neuvonen,et al.  Itraconazole increases but grapefruit juice greatly decreases plasma concentrations of celiprolol , 2003, Clinical pharmacology and therapeutics.

[4]  A. Olyaei,et al.  Effect of grapefruit juice on cyclosporin A pharmacokinetics in pediatric renal transplant patients , 2000, Pediatric transplantation.

[5]  Á. Balogh,et al.  Can grapefruit juice influence ethinylestradiol bioavailability? , 1996, Contraception.

[6]  Y Zhang,et al.  The Gut as a Barrier to Drug Absorption , 2001, Clinical pharmacokinetics.

[7]  U. Fuhr,et al.  Effects of grapefruit juice and smoking on verapamil concentrations in steady state , 2002, European Journal of Clinical Pharmacology.

[8]  H. Dieperink,et al.  Effect of grapefruit juice on Sandimmun Neoral absorption among stable renal allograft recipients. , 2001, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[9]  M. Jann,et al.  Effect of Seville Orange Juice and Grapefruit Juice on Indinavir Pharmacokinetics , 2002, Journal of clinical pharmacology.

[10]  J. Vanakoski,et al.  PHARMACOKINETICS AND DISPOSITION , 2022 .

[11]  E. Nicolosi,et al.  Citrus phylogeny and genetic origin of important species as investigated by molecular markers , 2000, Theoretical and Applied Genetics.

[12]  U. Fuhr,et al.  Inhibitory effect of grapefruit juice and its bitter principal, naringenin, on CYP1A2 dependent metabolism of caffeine in man. , 1993, British journal of clinical pharmacology.

[13]  G R Wilkinson,et al.  OATP and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine. , 1999, Drug metabolism and disposition: the biological fate of chemicals.

[14]  S. H. Lee,et al.  Repeated ingestion of grapefruit juice does not alter clozapine's steady-state plasma levels, effectiveness, and tolerability. , 2001, The Journal of clinical psychiatry.

[15]  A. Schinkel.  The roles of P-glycoprotein and MRP1 in the blood-brain and blood-cerebrospinal fluid barriers. , 2001, Advances in experimental medicine and biology.

[16]  T. Terao,et al.  Grapefruit Juice-fluvoxamine Interaction: Is It Risky Or Not? , 2003, Journal of clinical psychopharmacology.

[17]  C. Eap,et al.  Effects of grapefruit juice on the pharmacokinetics of the enantiomers of methadone , 2004, Clinical pharmacology and therapeutics.

[18]  I. Wainer,et al.  The effect of grapefruit juice and seville orange juice on the pharmacokinetics of dextromethorphan: the role of gut CYP3A and P-glycoprotein. , 2002, Life sciences.

[19]  D. Greenblatt,et al.  Time course of recovery of cytochrome p450 3A function after single doses of grapefruit juice , 2003, Clinical pharmacology and therapeutics.

[20]  P. Neuvonen,et al.  Orange juice substantially reduces the bioavailability of the β‐adrenergic–blocking agent celiprolol , 2004, Clinical pharmacology and therapeutics.

[21]  P. Gubbins,et al.  Grapefruit juice decreases the systemic availability of itraconazole capsules in healthy volunteers. , 1999, Therapeutic drug monitoring.

[22]  K. Sugawara,et al.  The effects of grapefruit juice on the pharmacokinetics of erythromycin , 2001, European Journal of Clinical Pharmacology.

[23]  L. Benet,et al.  Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P‐glycoprotein: Implications for drug delivery and activity in cancer chemotherapy , 1995, Molecular carcinogenesis.

[24]  P. Watkins,et al.  Drug interactions with herbal products and grapefruit juice: A conference report , 2004, Clinical pharmacology and therapeutics.

[25]  S. Krähenbühl,et al.  Grapefruit juice enhances the bioavailability of the HIV protease inhibitor saquinavir in man. , 1998, British journal of clinical pharmacology.

[26]  W. Gaus,et al.  Pharmacokinetic Herb-Drug Interactions: Are Preventive Screenings Necessary and Appropriate? , 2004, Planta medica.

[27]  M. Shelton,et al.  Effects of Grapefruit Juice on Pharmacokinetic Exposure to Indinavir in HIV‐Positive Subjects , 2001, Journal of clinical pharmacology.

[28]  G. Jang,et al.  Dietary Effects on Drug Metabolism and Transport , 2003, Clinical pharmacokinetics.

[29]  S. Krähenbühl,et al.  Interaction between grapefruit juice and midazolam in humans , 1995, Clinical pharmacology and therapeutics.

[30]  Y. Sawada,et al.  Inhibition of vinblastine efflux mediated by P-glycoprotein by grapefruit juice components in caco-2 cells. , 1998, Biological & pharmaceutical bulletin.

[31]  L. Lim,et al.  Modulation of Digoxin Transport Across Caco-2 Cell Monolayers by Citrus Fruit Juices: Lime, Lemon, Grapefruit, and Pummelo , 2003, Pharmaceutical Research.

[32]  C. Mckinstry,et al.  Quercetin, an in vitro inhibitor of CYP3A, does not contribute to the interaction between nifedipine and grapefruit juice. , 1993, British journal of clinical pharmacology.

[33]  W. Hauck,et al.  Exposure‐Dependent Inhibition of Intestinal and Hepatic CYP3A4 In Vivo by Grapefruit Juice , 2003, Journal of clinical pharmacology.

[34]  Tsuyoshi Mikkaichi,et al.  The organic anion transporter (OATP) family. , 2004, Drug metabolism and pharmacokinetics.

[35]  F. Greenway,et al.  The effects of grapefruit on weight and insulin resistance: relationship to the metabolic syndrome. , 2006, Journal of medicinal food.

[36]  S. Kaneko,et al.  Effects of grapefruit juice on the pharmacokinetics of pitavastatin and atorvastatin. , 2005, British journal of clinical pharmacology.

[37]  P. Neuvonen,et al.  Duration of effect of grapefruit juice on the pharmacokinetics of the CYP3A4 substrate simvastatin , 2000, Clinical pharmacology and therapeutics.

[38]  C. Regårdh,et al.  Effects of grapefruit juice ingestion – pharmacokinetics and haemodynamics of intravenously and orally administered felodipine in healthy men , 1997, European Journal of Clinical Pharmacology.

[39]  S. Vandel,et al.  Plasma levels of clozapine and desmethylclozapine are unaffected by concomitant ingestion of grapefruit juice , 2000, European Journal of Clinical Pharmacology.

[40]  R. Koopmans,et al.  Effect of grapefruit juice or cimetidine coadministration on albendazole bioavailability. , 2002, The American journal of tropical medicine and hygiene.

[41]  P. Neuvonen,et al.  Effect of grapefruit juice dose on grapefruit juice–triazolam interaction: repeated consumption prolongs triazolam half-life , 2000, European Journal of Clinical Pharmacology.

[42]  W. Bennett,et al.  Interaction Between Cyclosporine and Grapefruit Juice Requires Long‐Term Ingestion in Stable Renal Transplant Recipients , 1998, Pharmacotherapy.

[43]  U. Fuhr,et al.  Effects of grapefruit juice on the pharmacokinetics of sildenafil , 2002, Clinical pharmacology and therapeutics.

[44]  Y. Sawada,et al.  Effects of Grapefruit Juice and Orange Juice on the Intestinal Efflux of P-Glycoprotein Substrates , 2004, Pharmaceutical Research.

[45]  T. Ohta,et al.  Role of furanocoumarin derivatives on grapefruit juice-mediated inhibition of human CYP3A activity. , 2000, Drug metabolism and disposition: the biological fate of chemicals.

[46]  P. Thomas,et al.  Inhibition and kinetics of cytochrome P4503A activity in microsomes from rat, human, and cdna-expressed human cytochrome P450. , 1996, Drug metabolism and disposition: the biological fate of chemicals.

[47]  P. Neuvonen,et al.  Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin , 1999, Clinical pharmacology and therapeutics.

[48]  D. M. Sullivan,et al.  Grapefruit juice and the response to warfarin. , 1998, American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists.

[49]  D. Min,et al.  Effect of grapefruit juice on cyclosporine pharmacokinetics in renal transplant patients. , 1996, Transplantation.

[50]  P. Langguth,et al.  Grapefruit juice enhances intestinal absorption of the P-glycoprotein substrate talinolol. , 2001, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[51]  T. Hidaka,et al.  Effect of grapefruit juice on pharmacokinetics of itraconazole in healthy subjects. , 1998, International journal of clinical pharmacology and therapeutics.

[52]  P. Neuvonen,et al.  Plasma concentrations of triazolam are increased by concomitant ingestion of grapefruit juice , 1995, Clinical pharmacology and therapeutics.

[53]  D. Min,et al.  Effect of Grapefruit Juice on Pharmacokinetics of Microemulsion Cyclosporine in African American Subjects Compared with Caucasian Subjects: Does Ethnic Difference Matter? , 2001, Journal of clinical pharmacology.

[54]  R. Weintraub,et al.  Drug Interactions with Grapefruit Juice , 1997, Clinical pharmacokinetics.

[55]  C. Peloquin,et al.  Effect of Grapefruit Juice on Clarithromycin Pharmacokinetics , 1998, Antimicrobial Agents and Chemotherapy.

[56]  R. B. Parker,et al.  Effects of Grapefruit Juice on Intestinal P‐glycoprotein: Evaluation Using Digoxin in Humans , 2003, Pharmacotherapy.

[57]  T. Ishizaki,et al.  Effects of grapefruit juice on the stereoselective disposition of nicardipine in humans: evidence for dominant presystemic elimination at the gut site , 2000, European Journal of Clinical Pharmacology.

[58]  P. Ryan,et al.  Dosing implications of a clinical interaction between grapefruit juice and cyclosporine and metabolite concentrations in patients with autoimmune diseases. , 1997, The Journal of rheumatology.

[59]  D. Greenblatt,et al.  Effect of extended exposure to grapefruit juice on cytochrome P450 3A activity in humans: Comparison with ritonavir , 2006, Clinical pharmacology and therapeutics.

[60]  U. Fuhr,et al.  Grapefruit juice increases oral nimodipine bioavailability. , 1998, International journal of clinical pharmacology and therapeutics.

[61]  Y. Sawada,et al.  CITRUS JUICES INHIBIT THE FUNCTION OF HUMAN ORGANIC ANION-TRANSPORTING POLYPEPTIDE OATP-B , 2005, Drug Metabolism and Disposition.

[62]  M. Matsumoto,et al.  Undesirable Effects of Citrus Juice on the Pharmacokinetics of Drugs , 2005, Drug safety.

[63]  J. Sotelo,et al.  Interaction between Grapefruit Juice and Praziquantel in Humans , 2002, Antimicrobial Agents and Chemotherapy.

[64]  D. Bailey,et al.  Effect of grapefruit juice and naringin on nisoldipine pharmacokinetics , 1993, Clinical pharmacology and therapeutics.

[65]  G. Dresser,et al.  Grapefruit juice–felodipine interaction in the elderly , 2000, Clinical pharmacology and therapeutics.

[66]  T. Tsuruo,et al.  Effect of bioflavonoids on vincristine transport across blood-brain barrier. , 2000, European journal of pharmacology.

[67]  S. Larsen,et al.  Intestinal first pass metabolism of midazolam in liver cirrhosis --effect of grapefruit juice. , 2002, British journal of clinical pharmacology.

[68]  D. Bailey,et al.  Erythromycin‐felodipine interaction: Magnitude, mechanism, and comparison with grapefruit juice , 1996, Clinical pharmacology and therapeutics.

[69]  J. Lipsky,et al.  Drug-grapefruit juice interactions. , 2000, Mayo Clinic proceedings.

[70]  Samir K. Gupta,et al.  Grapefruit Juice Reduces the Oral Bioavailability of Fexofenadine But Not Desloratadine , 2002, Clinical pharmacokinetics.

[71]  M. Gralak,et al.  Changes in plasma lipid and antioxidant activity in rats as a result of naringin and red grapefruit supplementation. , 2005, Journal of agricultural and food chemistry.

[72]  Y. Sawada,et al.  Effect of furanocoumarin derivatives in grapefruit juice on the uptake of vinblastine by Caco‐2 cells and on the activity of cytochrome P450 3A4 , 2000, British journal of pharmacology.

[73]  D. Min,et al.  Effect of Grapefruit Juice on the Pharmacokinetics and Pharmacodynamics of Quinidine in Healthy Volunteers , 1996, Journal of clinical pharmacology.

[74]  K. Brøsen,et al.  Effect of diclofenac, disulfiram, itraconazole, grapefruit juice and erythromycin on the pharmacokinetics of quinidine. , 1999, British journal of clinical pharmacology.

[75]  P. Ho,et al.  Effect of grapefruit juice on pharmacokinetics and pharmacodynamics of verapamil enantiomers in healthy volunteers , 2000, European Journal of Clinical Pharmacology.

[76]  C. Funck-Brentano,et al.  Effect of grapefruit juice on digoxin pharmacokinetics in humans , 2001, Clinical pharmacology and therapeutics.

[77]  K. Brøsen,et al.  The impact of CYP2C8 polymorphism and grapefruit juice on the pharmacokinetics of repaglinide. , 2006, British journal of clinical pharmacology.

[78]  A. Dahan,et al.  Food–drug interaction: grapefruit juice augments drug bioavailability—mechanism, extent and relevance , 2004, European Journal of Clinical Nutrition.

[79]  A. Harralson,et al.  The effects of grapefruit juice on sertraline metabolism: an in vitro and in vivo study. , 1999, Clinical therapeutics.

[80]  D. Bailey,et al.  Grapefruit juice-drug interactions. , 1998, British journal of clinical pharmacology.

[81]  J. Potter,et al.  Vegetables, fruit, and cancer prevention: a review. , 1996, Journal of the American Dietetic Association.

[82]  D. Wortham,et al.  Grapefruit Juice Alters the Systemic Bioavailability and Cardiac Repolarization of Terfenadine in Poor Metabolizers of Terfenadine , 1996, Journal of clinical pharmacology.

[83]  R. Bergstrand,et al.  Acute effects of drinking grapefruit juice on the pharmacokinetics and dynamics on felodipine — and its potential clinical relevance , 2004, European Journal of Clinical Pharmacology.

[84]  D. Lowenthal,et al.  Effect of grapefruit juice on blood cyclosporin concentration , 1995, The Lancet.

[85]  S. Garg,et al.  Effect of grapefruit juice on carbamazepine bioavailability in patients with epilepsy , 1998, Clinical pharmacology and therapeutics.

[86]  A. Taburet,et al.  Single-Dose Pharmacokinetics of Amprenavir Coadministered with Grapefruit Juice , 2002, Antimicrobial Agents and Chemotherapy.

[87]  D. Bailey,et al.  Grapefruit juice–felodipine interaction: Mechanism, predictability, and effect of naringin , 1993, Clinical pharmacology and therapeutics.

[88]  D. Min,et al.  Effect of Grapefruit Juice on the Pharmacokinetics of Microemulsion Cyclosporine and its Metabolite in Healthy Volunteers: Does the Formulation Difference Matter? , 1998, Journal of clinical pharmacology.

[89]  E. Lentjes,et al.  The effect of grapefruit juice on cyclosporine and prednisone metabolism in transplant patients , 1995, Clinical pharmacology and therapeutics.

[90]  C. Daher,et al.  Effect of acute and chronic grapefruit, orange, and pineapple juice intake on blood lipid profile in normolipidemic rat. , 2005, Medical science monitor : international medical journal of experimental and clinical research.

[91]  G. Dresser,et al.  The effects of fruit juices on drug disposition: a new model for drug interactions , 2003, European journal of clinical investigation.

[92]  P. Neuvonen,et al.  Stereoselective pharmacokinetics of cisapride in healthy volunteers and the effect of repeated administration of grapefruit juice. , 2001, British journal of clinical pharmacology.

[93]  W. Tassaneeyakul,et al.  Formation of omeprazole sulphone but not 5-hydroxyomeprazole is inhibited by grapefruit juice. , 2000, British journal of clinical pharmacology.

[94]  J. Kumamoto,et al.  Contribution to the Origin of the Grapefruit, Citrus paradisi (Rutaceae) , 1982 .

[95]  S. Motomura,et al.  Effect of grapefruit juice on the disposition of manidipine enantiomers in healthy subjects. , 2006, British journal of clinical pharmacology.

[96]  S. Mertens-Talcott,et al.  Variation of flavonoids and furanocoumarins in grapefruit juices: a potential source of variability in grapefruit juice-drug interaction studies. , 2006, Journal of agricultural and food chemistry.

[97]  S. Garg,et al.  Lack of pharmacokinetic interaction between grapefruit juice and phenytoin in healthy male volunteers and epileptic patients. , 1999, Methods and findings in experimental and clinical pharmacology.

[98]  Lee Yong Lim,et al.  Herbal Modulation of P‐Glycoprotein , 2004, Drug metabolism reviews.

[99]  D. Greenblatt,et al.  Drug interactions with grapefruit juice: an update. , 2001, Journal of clinical psychopharmacology.

[100]  S. Chong,et al.  Effect of fruit juices on the oral bioavailability of fexofenadine in rats. , 2005, Journal of pharmaceutical sciences.

[101]  W. Tassaneeyakul,et al.  Inhibition selectivity of grapefruit juice components on human cytochromes P450. , 2000, Archives of biochemistry and biophysics.

[102]  W. Legrum,et al.  Metabolic and analytical interactions of grapefruit juice and 1,2-benzopyrone (coumarin) in man , 1996, European Journal of Clinical Pharmacology.

[103]  U. Fuhr,et al.  Lacking effect of grapefruit juice on theophylline pharmacokinetics. , 1995, International journal of clinical pharmacology and therapeutics.

[104]  T. Whitsett,et al.  Influence of Grapefruit Juice on Caffeine Pharmacokinetics and Pharmacodynamics , 1996, Pharmacotherapy.

[105]  W. Kirch,et al.  Influence of grapefruit juice on scopolamine pharmacokinetics and pharmacodynamics in healthy male and female subjects. , 2000, International journal of clinical pharmacology and therapeutics.

[106]  P. Neuvonen,et al.  Grapefruit juice—simvastatin interaction: Effect on serum concentrations of simvastatin, simvastatin acid, and HMG‐CoA reductase inhibitors , 1998, Clinical pharmacology and therapeutics.

[107]  P. Neuvonen,et al.  Effects of grapefruit juice on the absorption of levothyroxine. , 2005, British journal of clinical pharmacology.

[108]  D. Bailey,et al.  Grapefruit juice-felodipine interaction: reproducibility and characterization with the extended release drug formulation. , 1995, British journal of clinical pharmacology.

[109]  J. Spence.  Drug interactions with grapefruit: Whose responsibility is it to warn the public? , 1997, Clinical pharmacology and therapeutics.

[110]  H. Sigusch,et al.  Lack of effect of grapefruit juice on diltiazem bioavailability in normal subjects. , 1994, Die Pharmazie.

[111]  G. Dresser,et al.  Bergamottin, lime juice, and red wine as inhibitors of cytochrome P450 3A4 activity: Comparison with grapefruit juice , 2003, Clinical pharmacology and therapeutics.

[112]  K. Otani,et al.  Lack of significant pharmacokinetic interaction between haloperidol and grapefruit juice. , 1999, International clinical psychopharmacology.

[113]  S. Soback,et al.  The effect of grapefruit juice on the pharmacokinetics of orally administered verapamil , 1998, European Journal of Clinical Pharmacology.

[114]  A. Schinkel,et al.  Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview. , 2003, Advanced drug delivery reviews.

[115]  C. Funck-Brentano,et al.  Pharmacokinetic and pharmacodynamic interaction between grapefruit juice and halofantrine , 2002, Clinical pharmacology and therapeutics.

[116]  Jamie J. Zhao,et al.  Grapefruit juice has minimal effects on plasma concentrations of lovastatin‐derived 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors , 1999, Clinical pharmacology and therapeutics.

[117]  K. Otani,et al.  Effects of repeated ingestion of grapefruit juice on the single and multiple oral-dose pharmacokinetics and pharmacodynamics of alprazolam , 2000, Psychopharmacology.

[118]  J. Nezu,et al.  Involvement of Human Organic Anion Transporting Polypeptide OATP-B (SLC21A9) in pH-Dependent Transport across Intestinal Apical Membrane , 2003, Journal of Pharmacology and Experimental Therapeutics.

[119]  Wilhelm Kirch,et al.  Grapefruit Juice Ingestion Significantly Reduces Talinolol Bioavailability , 2005, Clinical pharmacology and therapeutics.

[120]  R. van Leusen,et al.  Saquinavir soft-gel capsules (Fortovase®) give lower exposure than expected, even after a high-fat breakfast , 2002, Pharmacy World and Science.

[121]  D. Back,et al.  Inhibition of the CYP3A4-mediated metabolism and P-glycoprotein-mediated transport of the HIV-1 protease inhibitor saquinavir by grapefruit juice components. , 1999, British journal of clinical pharmacology.

[122]  A. Boobis,et al.  The cardiac effects of terfenadine after inhibition of its metabolism by grapefruit juice , 1997, European Journal of Clinical Pharmacology.

[123]  M. V. van Agtmael,et al.  Grapefruit juice increases the bioavailability of artemether , 1999, European Journal of Clinical Pharmacology.

[124]  P. Neuvonen,et al.  Effects of grapefruit juice on the pharmacokinetics of acebutolol. , 2005, British journal of clinical pharmacology.

[125]  P. Dawson,et al.  Fruit juices inhibit organic anion transporting polypeptide–mediated drug uptake to decrease the oral availability of fexofenadine , 2002, Clinical pharmacology and therapeutics.

[126]  Morton B. Brown,et al.  Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression. , 1997, The Journal of clinical investigation.

[127]  P. Neuvonen,et al.  Grapefruit juice substantially increases plasma concentrations of buspirone , 1998, Clinical pharmacology and therapeutics.

[128]  P. Neuvonen,et al.  Effects of regular consumption of grapefruit juice on the pharmacokinetics of simvastatin. , 2004, British journal of clinical pharmacology.

[129]  R. Kim,et al.  Organic anion‐transporting polypeptide (OATP) transporter family and drug disposition , 2003, European journal of clinical investigation.

[130]  P. Watkins,et al.  6′,7′‐Dihydroxybergamottin in grapefruit juice and Seville orange juice: Effects on cyclosporine disposition, enterocyte CYP3A4, and P‐glycoprotein , 1999, Clinical pharmacology and therapeutics.

[131]  Shufeng Zhou,et al.  Therapeutic drugs that behave as mechanism-based inhibitors of cytochrome P450 3A4. , 2004, Current drug metabolism.

[132]  P. Neuvonen,et al.  Repeated consumption of grapefruit juice considerably increases plasma concentrations of cisapride , 1999, Clinical pharmacology and therapeutics.

[133]  M. Ducharme,et al.  Trough concentrations of cyclosporine in blood following administration with grapefruit juice. , 1993, British journal of clinical pharmacology.

[134]  R. Scora,et al.  On the History and Origin of Citrus , 1975 .

[135]  G. Kearns,et al.  Ibuprofen pharmacokinetics in preterm infants with patent ductus arteriosus , 2001 .

[136]  T. Hedner,et al.  Inhibition of 17 beta-estradiol metabolism by grapefruit juice in ovariectomized women. , 1994, Maturitas.

[137]  B. Edgar,et al.  Grapefruit juice and cimetidine inhibit stereoselective metabolism of nitrendipine in humans , 1991, Clinical pharmacology and therapeutics.

[138]  U. Christians,et al.  Grapefruit Juice Activates P-Glycoprotein-Mediated Drug Transport , 1999, Pharmaceutical Research.

[139]  C. Libersa,et al.  Dramatic inhibition of amiodarone metabolism induced by grapefruit juice. , 2000, British journal of clinical pharmacology.

[140]  P. Watkins,et al.  PHARMACOKINETICS AND DRUG DISPOSITION Seville orange juice-felodipine interaction: Comparison with dilute grapefruit juice and involvement of furocoumarins , 2001 .

[141]  Y. Sawada,et al.  Relationship between time after intake of grapefruit juice and the effect on pharmacokinetics and pharmacodynamics of nisoldipine in healthy subjects , 2000, Clinical pharmacology and therapeutics.

[142]  G. Block,et al.  Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence. , 1992, Nutrition and cancer.

[143]  T. Tsuruo,et al.  Inhibition of P-glycoprotein by orange juice components, polymethoxyflavones in adriamycin-resistant human myelogenous leukemia (K562/ADM) cells. , 2000, Cancer letters.

[144]  G. Foulds,et al.  Lack of effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of amlodipine. , 2000, British journal of clinical pharmacology.

[145]  P. Neuvonen,et al.  Grapefruit juice can increase the plasma concentrations of oral methylprednisolone , 2000, European Journal of Clinical Pharmacology.

[146]  J. Hagenbach,et al.  In vitro inhibition of simvastatin metabolism in rat and human liver by naringenin. , 1999, Life sciences.

[147]  P. Watkins,et al.  Mechanisms of enhanced oral availability of CYP3A4 substrates by grapefruit constituents. Decreased enterocyte CYP3A4 concentration and mechanism-based inactivation by furanocoumarins. , 1997, Drug metabolism and disposition: the biological fate of chemicals.

[148]  A. Folsom,et al.  Dietary catechins in relation to coronary heart disease death among postmenopausal women , 2001, Epidemiology.

[149]  J. Spence,et al.  Pharmacokinetic-Pharmacodynamic Consequences and Clinical Relevance of Cytochrome P450 3A4 Inhibition , 2000, Clinical pharmacokinetics.

[150]  W. Legrum,et al.  The character of inhibition of the metabolism of 1,2-benzopyrone (coumarin) by grapefruit juice in human , 1997, European Journal of Clinical Pharmacology.

[151]  H. Sigusch,et al.  Influence of grapefruit juice on the pharmacokinetics of a slow release nifedipine formulation. , 1994, Die Pharmazie.

[152]  G. Dresser,et al.  Interactions Between Grapefruit Juice and Cardiovascular Drugs , 2004, American journal of cardiovascular drugs : drugs, devices, and other interventions.

[153]  G. Dresser,et al.  Grapefruit‐felodipine interaction: Effect of unprocessed fruit and probable active ingredients , 2000, Clinical pharmacology and therapeutics.

[154]  Eiji Uchida,et al.  Effects of grapefruit juice on pharmacokinetics of atorvastatin and pravastatin in Japanese. , 2004, British journal of clinical pharmacology.

[155]  H. Sigusch,et al.  Grapefruit juice inhibits 7-hydroxylation of coumarin in healthy volunteers , 2004, European Journal of Clinical Pharmacology.

[156]  T. Ohta,et al.  Inhibitory effect of natural furanocoumarins on human microsomal cytochrome P450 3A activity. , 2000, Japanese journal of pharmacology.

[157]  G. Montay,et al.  Effects of Itraconazole or Grapefruit Juice on the Pharmacokinetics of Telithromycin , 2005, Pharmacotherapy.

[158]  A. Fujimura,et al.  Interaction between grapefruit juice and hypnotic drugs: comparison of triazolam and quazepam , 2004, European Journal of Clinical Pharmacology.

[159]  D. K. Williams,et al.  Influence of Grapefruit Juice on the Systemic Availability of Itraconazole Oral Solution in Healthy Adult Volunteers , 2004, Pharmacotherapy.

[160]  D. Min,et al.  Determination of Sildenafil Citrate in Plasma by High-Performance Liquid Chromatography and a Case for the Potential Interaction of Grapefruit Juice With Sildenafil Citrate , 2001, Therapeutic drug monitoring.

[161]  Amy Roe,et al.  The Conduct of In Vitro and In Vivo Drug‐Drug Interaction Studies: A PhRMA Perspective , 2003, Journal of clinical pharmacology.

[162]  P. Woster,et al.  Bergamottin contribution to the grapefruit juice–felodipine interaction and disposition in humans , 2004, Clinical pharmacology and therapeutics.

[163]  G. Dresser,et al.  Red wine–cisapride interaction: Comparison with grapefruit juice , 2001, Clinical pharmacology and therapeutics.

[164]  I. Pastan,et al.  Biochemical, cellular, and pharmacological aspects of the multidrug transporter. , 1999, Annual review of pharmacology and toxicology.

[165]  M. Agtmael,et al.  The effect of grapefruit juice on the time‐dependent decline of artemether plasma levels in healthy subjects , 1999, Clinical pharmacology and therapeutics.

[166]  R. Benton,et al.  Grapefruit juice alters terfenadine pharmacokinetics, resulting in prolongation of repolarization on the electrocardiogram , 1996, Clinical pharmacology and therapeutics.

[167]  J. Potter,et al.  Vegetables, fruit, and cancer. I. Epidemiology , 1991, Cancer Causes & Control.

[168]  H. McLeod,et al.  Effect of grapefruit juice intake on etoposide bioavailability , 2002, European Journal of Clinical Pharmacology.

[169]  A. S. Gross,et al.  Influence of grapefruit juice on cisapride pharmacokinetics , 1999, Clinical pharmacology and therapeutics.

[170]  P. Neuvonen,et al.  Grapefruit juice greatly increases serum concentrations of lovastatin and lovastatin acid , 1998, Clinical pharmacology and therapeutics.

[171]  P. Watkins,et al.  A furanocoumarin-free grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juice-felodipine interaction. , 2006, The American journal of clinical nutrition.

[172]  A. Åsberg,et al.  Intake of grapefruit juice alters the metabolic pattern of cyclosporin A in renal transplant recipients. , 2002, International journal of clinical pharmacology and therapeutics.

[173]  P. Watkins,et al.  6′7′‐Dihydroxybergamottin Contributes to the Grapefruit Juice Effect , 2004, Clinical pharmacology and therapeutics.

[174]  J. Ahlner,et al.  Effect of grapefruit juice on the pharmacokinetics of amlodipine in healthy volunteers , 1996, European Journal of Clinical Pharmacology.

[175]  P. Watkins,et al.  TWO MAJOR GRAPEFRUIT JUICE COMPONENTS DIFFER IN INTESTINAL CYP3A4 INHIBITION KINETIC AND BINDING PROPERTIES , 2004, Drug Metabolism and Disposition.

[176]  D. Bailey,et al.  Interaction of citrus juices with felodipine and nifedipine , 1991, The Lancet.

[177]  E. Scapa,et al.  Effect of Grapefruit Juice on the Pharmacokinetics of Losartan and Its Active Metabolite E3174 in Healthy Volunteers , 2001, Therapeutic drug monitoring.

[178]  P. Artursson,et al.  Transport of celiprolol across human intestinal epithelial (Caco‐2) cells: mediation of secretion by multiple transporters including P‐glycoprotein , 1993, British journal of pharmacology.

[179]  I. Pastan,et al.  Biochemistry of multidrug resistance mediated by the multidrug transporter. , 1993, Annual review of biochemistry.

[180]  M. Ducharme,et al.  Disposition of intravenous and oral cyclosporine after administration with grapefruit juice , 1995, Clinical pharmacology and therapeutics.

[181]  Bruno Stieger,et al.  Enterohepatic bile salt transporters in normal physiology and liver disease. , 2004, Gastroenterology.

[182]  P. Ho,et al.  Grapefruit juice has no effect on quinine pharmacokinetics , 1999, European Journal of Clinical Pharmacology.

[183]  A. Åsberg,et al.  Coadministration of grapefruit juice increases systemic exposure of diltiazem in healthy volunteers , 2002, European Journal of Clinical Pharmacology.

[184]  Y. Sawada,et al.  Pharmacokinetic analysis of felodipine-grapefruit juice interaction based on an irreversible enzyme inhibition model. , 2000, British journal of clinical pharmacology.

[185]  K. He,et al.  Inactivation of cytochrome P450 3A4 by bergamottin, a component of grapefruit juice. , 1998, Chemical research in toxicology.

[186]  C. Regårdh,et al.  The interaction effect of grapefruit juice is maximal after the first glass , 1998, European Journal of Clinical Pharmacology.

[187]  J. Azuma,et al.  Interaction of citrus juices with pranidipine, a new 1,4-dihydropyridine calcium antagonist, in healthy subjects , 1998, European Journal of Clinical Pharmacology.