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David G. Bailey - One of the best experts on this subject based on the ideXlab platform.
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Grapefruit Juice ingestion reduces talinolol serum concentration
Clinical Pharmacology & Therapeutics, 2005Co-Authors: Ute I. Schwarz, Reinhard Oertel, David G. Bailey, Diana Seemann, Stephan Miehlke, Eberhard Kuhlisch, Martin F. Fromm, Richard B. Kim, Wilhelm KirchAbstract:Background/Aim The objective was to evaluate the effect of single and repeated Grapefruit Juice relative to water on oral pharmacokinetics (PK) of the non-metabolized and P-glycoprotein (Pgp)-transported drug talinolol in humans, and to assess the impact of Grapefruit Juice on Pgp and intestinal uptake transporters. Methods Oral PK of 50mg talinolol was determined with water, single (300mL), and repeated Grapefruit Juice intake (6 days, 900mL/day) in 24 healthy Caucasians. MDR1 mRNA and Pgp levels were measured in duodenal biopsies of 3 subjects before and after Juice. All subjects were genotyped for three MDR1 polymorphisms (1236C>T, 2677G>T/A, 3435C>T). Results Single Grapefruit Juice decreased the talinolol AUC, Cmax, and urinary excretion values to 56% (P
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Grapefruit Juice ingestion significantly reduces talinolol bioavailability.
Clinical pharmacology and therapeutics, 2005Co-Authors: Ute I. Schwarz, Reinhard Oertel, David G. Bailey, Diana Seemann, Stephan Miehlke, Eberhard Kuhlisch, Martin F. Fromm, Richard B. Kim, Wilhelm KirchAbstract:Objectives Our objectives were to evaluate the effect of single and repeated Grapefruit Juice ingestion relative to water on the oral pharmacokinetics of the nonmetabolized and P-glycoprotein-transported drug talinolol in humans and to assess the potential impact of Grapefruit Juice ingestion on P-glycoprotein and intestinal uptake transporters. Methods The oral pharmacokinetics of 50 mg talinolol was determined with water, with 1 glass of Grapefruit Juice (300 mL), and after 6 days of repeated Grapefruit Juice ingestion (900 mL/d) in 24 healthy white volunteers. MDR1 messenger ribonucleic acid and P-glycoprotein levels were measured in duodenal biopsy specimens obtained from 3 individuals before and after ingestion of Grapefruit Juice. Three commonly occurring polymorphisms in the MDR1 gene were also assessed. Results A single glass of Grapefruit Juice decreased the talinolol area under the serum concentration-time curve (AUC), peak serum drug concentration (Cmax), and urinary excretion values to 56% (P < .001), 57% (P < .001), and 56% (P < .001), respectively, of those with water. Repeated ingestion of Grapefruit Juice had a similar effect (44% to 65% reduction; P < .01). Single or repeated Juice ingestion did not affect renal clearance, elimination half-life, or time to reach Cmax (tmax). MDR1 messenger ribonucleic acid and P-glycoprotein levels in duodenal biopsy specimens were not affected by Grapefruit Juice. MDR1 genotypes (C1236T, G2677T/A, and C3435T) were not associated with altered talinolol pharmacokinetics. Conclusion Because both single and repeated ingestion of Grapefruit Juice lowered rather than increased talinolol AUC, our findings suggest that constituents in Grapefruit Juice preferentially inhibited an intestinal uptake process rather than P-glycoprotein. Moreover, Grapefruit Juice did not alter intestinal P-glycoprotein expression. Clinical Pharmacology & Therapeutics (2005) 77, 291–301; doi: 10.1016/j.clpt.2004.11.111
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Grapefruit Juice-drug interactions. Commentary. Author's reply
British Journal of Clinical Pharmacology, 2004Co-Authors: David G. Bailey, J. David Spence, J. Malcolm, O. Arnold, Uwe FuhrAbstract:The novel finding that Grapefruit Juice can markedly augment oral drug bioavailability was based on an unexpected observation from an interaction study between the dihydropyridine calcium channel antagonist, felodipine, and ethanol in which Grapefruit Juice was used to mask the taste of the ethanol. Subsequent investigations showed that Grapefruit Juice acted by reducing presystemic felodipine metabolism through selective post-translational down regulation of cytochrome P450 3A4 (CYP3A4) expression in the intestinal wall. Since the duration of effect of Grapefruit Juice can last 24 h, repeated Juice consumption can result in a cumulative increase in felodipine AUC and C max . The high variability of the magnitude of effect among individuals appeared dependent upon inherent differences in enteric CYP3A4 protein expression such that individuals with highest baseline CYP3A4 had the highest proportional increase. At least 20 other drugs have been assessed for an interaction with Grapefruit Juice. Medications with innately low oral bioavailability because of substantial presystemic metabolism mediated by CYP3A4 appear affected by Grapefruit Juice. Clinically relevant interactions seem likely for most dihydropyridines, terfenadine, saquinavir, cyclosporin, midazolam, triazolam and verapamil and may also occur with lovastatin, cisapride and astemizole. The importance of the interaction appears to be influenced by individual patient susceptibility, type and amount of Grapefruit Juice and administration-related factors. Although in vitro findings support the flavonoid, naringin, or the furanocoumarin, 6',7'-dihydroxybergamottin, as being active ingredients, a recent investigation indicated that neither of these substances made a major contribution to Grapefruit Juice-drug interactions in humans.
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Interactions Between Grapefruit Juice and Cardiovascular Drugs
American journal of cardiovascular drugs : drugs devices and other interventions, 2004Co-Authors: David G. Bailey, George K. DresserAbstract:Grapefruit Juice can alter oral drug pharmacokinetics by different mechanisms. Irreversible inactivation of intestinal cytochrome P450 (CYP) 3A4 is produced by commercial Grapefruit Juice given as a single normal amount (e. g. 200–300mL) or by whole fresh fruit segments. As a result, presystemic metabolism is reduced and oral drug bioavailability increased. Enhanced oral drug bioavailability can occur 24 hours after Juice consumption. Inhibition of P-glycoprotein (P-gp) is a possible mechanism that increases oral drug bioavailability by reducing intestinal and/or hepatic efflux transport. Recently, inhibition of organic anion transporting polypeptides by Grapefruit Juice was observed in vitro; intestinal uptake transport appeared decreased as oral drug bioavailability was reduced.
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Grapefruit Juice–felodipine interaction in the elderly
Clinical pharmacology and therapeutics, 2000Co-Authors: George K. Dresser, David G. Bailey, S. George CarruthersAbstract:Background Grapefruit Juice can increase the oral bioavailability of a broad range of medications. This interaction has not been assessed in the elderly. Methods Twelve healthy elderly people (70 to 83 years of age) were administered 5 mg felodipine extended release with 250 mL Grapefruit Juice or water in a single-dose study. Subsequently, 6 of these people received 2.5 mg felodipine for 2 days, followed by 5 mg felodipine for 6 days with 250 mL Grapefruit Juice or water in a steady-state study. Plasma concentrations of felodipine and dehydrofelodipine metabolite, blood pressure, and heart rate were measured over 24 hours after single and final steady-state dose. Results Mean felodipine area under the curve and maximum concentration were 2.9-fold and 4.0-fold greater, respectively, with Grapefruit Juice in both studies. Interindividual variability in the extent of the interaction was high. Felodipine apparent elimination half-life was not altered. Dehydrofelodipine area under the curve and maximum concentration were increased and dehydrofelodipine/felodipine area under the curve ratio was reduced. Systolic and diastolic blood pressures were lower with Grapefruit Juice in the single-dose study, whereas they were not different between treatments in the steady-state study. Curvilinear relationships existed between plasma felodipine concentration and changes in systolic and diastolic blood pressures. Heart rates were higher with Grapefruit Juice in both studies; however, this effect was greater and more prolonged at steady state. Conclusions A normal dietary amount of Grapefruit Juice produced a pronounced, unpredictable, and sustained pharmacokinetic interaction with felodipine by reducing its presystemic metabolism in the elderly. The different blood pressure results between the studies can be explained by felodipine concentration-blood pressure response relationships. The elderly should be particularly cautioned about concomitant Grapefruit Juice and felodipine ingestion. Clinical Pharmacology & Therapeutics (2000) 68, 28–34; doi: 10.1067/mcp.2000.107524
Kari T Kivisto - One of the best experts on this subject based on the ideXlab platform.
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Grapefruit Juice can increase the plasma concentrations of oral methylprednisolone.
European journal of clinical pharmacology, 2000Co-Authors: T Varis, Kari T Kivisto, Pertti J NeuvonenAbstract:To investigate whether the pharmacokinetics of orally administered methylprednisolone and plasma cortisol concentrations are affected by administration of Grapefruit Juice. In a randomised, two-phase, cross-over study, ten healthy subjects received either 200 ml double-strength Grapefruit Juice or water three times a day for 2 days. On day 3, 16 mg methylprednisolone was given orally with 200 ml Grapefruit Juice or water. Additionally, 200 ml Grapefruit Juice or water was ingested 0.5 h and 1.5 h after methylprednisolone administration. Plasma concentrations of methylprednisolone and cortisol were determined using liquid chromatography/mass spectrometry (LC/MS/MS) over a 47-h period. Grapefruit Juice increased the total area under the plasma methylprednisolone concentration-time curve (AUC 0--infinity) by 75% (P < 0.001) and the elimination half-life (t1/2) of methylprednisolone by 35% (P < 0.001). The peak plasma concentration of methylprednisolone (Cmax) was increased by 27% (P < 0.01). Grapefruit Juice delayed the time to the Cmax from 2.0 h to 3.0 h (P < 0.05). There was no significant difference in the plasma cortisol concentrations, measured after methylprednisolone administration, between the water and Grapefruit Juice phases. However, Grapefruit Juice slightly decreased the morning plasma cortisol concentrations before methylprednisolone administration (P < 0.05). Grapefruit Juice given in high amounts moderately increases the AUC 0--infinity and t1/2 of oral methylprednisolone. The increase in t1/2 suggests that Grapefruit Juice can affect the systemic methylprednisolone metabolism. The clinical significance of the Grapefruit Juice-methylprednisolone interaction is small, but in some sensitive subjects high doses of Grapefruit Juice might enhance the effects of oral methylprednisolone.
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effect of Grapefruit Juice dose on Grapefruit Juice triazolam interaction repeated consumption prolongs triazolam half life
European Journal of Clinical Pharmacology, 2000Co-Authors: Jari J Lilja, Kari T Kivisto, Janne T BackmanAbstract:Objective: Grapefruit Juice inhibits CYP3A4-mediated metabolism of several drugs during first pass. In this study, the effect of Grapefruit Juice dose on the extent of Grapefruit Juice–triazolam interaction was investigated.
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Duration of effect of Grapefruit Juice on the pharmacokinetics of the CYP3A4 substrate simvastatin
Clinical pharmacology and therapeutics, 2000Co-Authors: Jari J Lilja, Kari T KivistoAbstract:Background Grapefruit Juice is a potent inhibitor of CYP3A4-mediated drug metabolism. We wanted to investigate how long the inhibitory effect of Grapefruit Juice lasts, with the CYP3A4 substrate simvastatin used as a model drug. Methods This crossover study consisted of 5 study days, during which 10 healthy volunteers ingested 40 mg simvastatin with water (control), with “high-dose” Grapefruit Juice (200 mL double-strength Grapefruit Juice three times a day for 3 days), or 1, 3, and 7 days after ingestion of “high-dose” Grapefruit Juice. For safety reasons, the study was performed in three parts to allow simvastatin-free days between the study days. Serum concentrations of simvastatin and simvastatin acid were measured by liquid chromatography–tandem mass spectrometry up to 12 hours. Results When simvastatin was taken with Grapefruit Juice, the mean peak serum concentration (Cmax) and the mean area under the serum concentration-time curve [AUC(0-∞)] of simvastatin were increased 12.0-fold (P < .001) and 13.5-fold (P < .001), respectively, compared with control. When simvastatin was administered 24 hours after ingestion of the last dose of Grapefruit Juice, the Cmax and AUC(0-∞) were increased 2.4-fold (P < .01) and 2.1-fold (P < .001), respectively, compared with control. When simvastatin was given 3 days after ingestion of Grapefruit Juice, the Cmax and AUC(0-∞) were increased 1.5-fold (P = .12) and 1.4-fold (P = .09), respectively, compared with control. Seven days after ingestion of Grapefruit Juice, no differences in the Cmax or AUC(0-∞) of simvastatin were seen. The mean Cmax and AUC(0-∞) of simvastatin acid were increased 5.0-fold and 4.5-fold, respectively (P < .001), compared with control when simvastatin was taken with Grapefruit Juice and 1.7-fold (P < .01) when it was taken 24 hours after ingestion of Grapefruit Juice. After an interval of 3 or 7 days between ingestion of Grapefruit Juice and simvastatin, the pharmacokinetic variables of simvastatin acid did not differ significantly from those in the control phase. Conclusions When simvastatin is taken 24 hours after ingestion of “high-dose” Grapefruit Juice, the effect of Grapefruit Juice on the AUC of simvastatin is only about 10% of the effect observed during concomitant intake of Grapefruit Juice and simvastatin. The interaction potential of even high amounts of Grapefruit Juice with CYP3A4 substrates dissipates within 3 to 7 days after ingestion of the last dose of Grapefruit Juice. (Clin Pharmacol Ther 2000;68:384-90.) Clinical Pharmacology & Therapeutics (2000) 68, 384–390; doi: 10.1067/mcp.2000.110216
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Grapefruit Juice increases serum concentrations of atorvastatin and has no effect on pravastatin
Clinical Pharmacology & Therapeutics, 1999Co-Authors: Jari J Lilja, Kari T KivistoAbstract:Background Grapefruit Juice greatly increases the bioavailability of lovastatin and simvastatin. We studied the effect of Grapefruit Juice on the pharmacokinetics of atorvastatin and pravastatin. Methods Two randomized, two-phase crossover studies were performed—study I with atorvastatin in 12 healthy volunteers and study II with pravastatin in 11 healthy volunteers. In both studies, volunteers took 200 mL double-strength Grapefruit Juice or water three times a day for 2 days. On day 3, each subject ingested a single 40 mg dose of atorvastatin (study I) or pravastatin (study II) with either 200 mL Grapefruit Juice or water, and an additional 200 mL was ingested ½ hour and 1½ hours later. In addition, subjects took 200 mL Grapefruit Juice or water three times a day on days 4 and 5 in study I. In study I, serum concentrations of atorvastatin acid, atorvastatin lactone, 2-hydroxyatorvastatin acid, 2-hydroxyatorvastatin lactone, and active and total 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors were measured up to 72 hours. In study II, pravastatin, pravastatin lactone, and active and total HMG-CoA reductase inhibitors were measured up to 24 hours. Results Grapefruit Juice increased the area under the serum concentration–time curve of atorvastatin acid from time zero to 72 hours [AUC(0–72)] 2.5-fold (P < .01), whereas the peak serum concentration (Cmax) was not significantly changed. The time of the peak concentration (tmax) and the elimination half-life (t1/2) of atorvastatin acid were increased (P < .01). The AUC(0–72) of atorvastatin lactone was increased 3.3-fold (P < .01) and the Cmax 2.6-fold (P < .01) by Grapefruit Juice, and the tmax and t1/2 were also increased (P < .05). Grapefruit Juice decreased the Cmax (P < .001) and AUC(0–72) (P < .001) of 2-hydroxyatorvastatin acid and increased its tmax and t1/2 (P < .01). Grapefruit Juice also decreased the Cmax (P < .001) and AUC(0–72) (P < .05) of 2-hydroxyatorvastatin lactone. The AUC(0–72) values of active and total HMG-CoA reductase inhibitors were increased 1.3-fold (P < .05) and 1.5-fold (P < .01), respectively, by Grapefruit Juice. In study II, the only significant change observed in the pharmacokinetics of pravastatin was prolongation of the tmax of active HMG-CoA reductase inhibitors by Grapefruit Juice (P < .05). Conclusions Grapefruit Juice significantly increased serum concentrations of atorvastatin acid, atorvastatin lactone, and active and total HMG-CoA reductase inhibitors, probably by decreasing CYP3A4-mediated first-pass metabolism of atorvastatin in the small intestine. On the other hand, Grapefruit Juice had no effect on the pharmacokinetics of pravastatin. Concomitant use of atorvastatin and at least large amounts of Grapefruit Juice should be avoided, or the dose of atorvastatin should be reduced accordingly. Clinical Pharmacology & Therapeutics (1999) 66, 118–127; doi: 10.1053/cp.1999.v66.100453001
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Repeated consumption of Grapefruit Juice considerably increases plasma concentrations of cisapride
Clinical pharmacology and therapeutics, 1999Co-Authors: Kari T Kivisto, Janne T BackmanAbstract:Background Grapefruit Juice increases the bioavailability of several drugs that are metabolized during first pass by CYP3A4. In this study, the effect of Grapefruit Juice on the pharmacokinetics of orally administered cisapride was investigated. Methods In a randomized, two-phase crossover study, 10 healthy volunteers took either 200 mL double-strength Grapefruit Juice or water three times a day for 2 days. On day 3, each subject ingested 10 mg cisapride with either 200 mL Grapefruit Juice or water, and an additional 200 mL was ingested ½ hour and 1½ hours after cisapride administration. Timed blood samples were collected for 32 hours after cisapride intake, and a standard 12-lead ECG was recorded before the administration of cisapride and 2, 5, 8, and 12 hours later. Results The mean peak plasma concentration of cisapride was increased by 81% (range, 38% to 138%; P
Janne T Backman - One of the best experts on this subject based on the ideXlab platform.
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Effect of Grapefruit Juice on the bioactivation of prasugrel.
British journal of clinical pharmacology, 2015Co-Authors: Mikko T. Holmberg, Janne T Backman, Pertti J Neuvonen, Aleksi Tornio, Mikko Neuvonen, Hanna Hyvärinen, Mikko NiemiAbstract:Aims The P2Y12 inhibitor prasugrel is a prodrug, which is activated after its initial hydrolysis partly by cytochrome P450 (CYP) 3A4. Grapefruit Juice, a strong inactivator of intestinal CYP3A4, greatly reduces the activation and antiplatelet effects of clopidogrel. The aim of this study was to investigate the effects of Grapefruit Juice on prasugrel.
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Grapefruit Juice inhibits the metabolic activation of clopidogrel.
Clinical pharmacology and therapeutics, 2013Co-Authors: Mikko T. Holmberg, Janne T Backman, Aleksi Tornio, Mikko Neuvonen, Mikko NiemiAbstract:Cytochrome P450 (CYP) enzymes, including CYP2C19 and CYP3A4, participate in the bioactivation of clopidogrel. Grapefruit Juice constituents potently inactivate intestinal CYP3A4 and have been shown to inhibit CYP2C19 as well. In a randomized crossover study, 14 healthy volunteers ingested 200 ml of Grapefruit Juice or water three times daily for 3 days. On day 3, they ingested a single 600-mg dose of clopidogrel. Grapefruit Juice reduced the peak plasma concentration (Cmax) of the active metabolite of clopidogrel to 13% of the control (range 11–17%, P < 0.001) and the area under the plasma concentration–time curve from 0 to 3 h to 14% (range 12–17%, P < 0.001) of the control, but it had no significant effect on the parent clopidogrel. Moreover, Grapefruit Juice markedly decreased the platelet-inhibitory effect of clopidogrel, as assessed with the VerifyNow P2Y12 test in two of the participants. In conclusion, concomitant use of Grapefruit Juice may impair the efficacy of clopidogrel. Therefore, the use of Grapefruit Juice is best avoided during clopidogrel therapy. Clinical Pharmacology & Therapeutics (2014); 95 3, 307–313. doi:10.1038/clpt.2013.192
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itraconazole increases but Grapefruit Juice greatly decreases plasma concentrations of celiprolol
Clinical Pharmacology & Therapeutics, 2003Co-Authors: Jari J Lilja, Janne T Backman, Jouko Laitila, Harri Luurila, Pertti J NeuvonenAbstract:Objectives Our objective was to evaluate the effects of itraconazole and Grapefruit Juice on the pharmacokinetics of the β-adrenergic receptor-blocking agent celiprolol in healthy volunteers. Methods In a randomized 3-phase crossover study, 12 healthy volunteers took itraconazole 200 mg orally or placebo twice a day or 200 mL Grapefruit Juice 3 times a day for 2 days. On the morning of day 3, 1 hour after ingestion of itraconazole, placebo, or Grapefruit Juice, each subject ingested 100 mg celiprolol with 200 mL of water (placebo and itraconazole phases) or Grapefruit Juice. In addition, 200 mL of water or Grapefruit Juice was ingested 4 and 10 hours after celiprolol intake. The plasma concentrations of celiprolol, itraconazole, and hydroxyitraconazole and the excretion of celiprolol into urine were measured up to 33 hours after dosing. Systolic and diastolic blood pressures and heart rate were recorded with subjects in a sitting position before the administration of celiprolol and 2, 4, 6, and 10 hours later. Results During the itraconazole phase, the mean area under the plasma concentration-time curve from 0 to 33 hours [AUC(0–33)] of celiprolol was 80% greater (P < .05) than in the placebo phase. During the Grapefruit Juice phase, the mean AUC(0–33) and peak plasma concentration values of celiprolol were reduced to about 13% (P < .001) and 5% (P < .001) of the respective placebo phase values. The cumulative excretion into urine of celiprolol was increased by 59% by itraconazole (P < .05) and decreased by 85% by Grapefruit Juice (P < .001). Hemodynamic variables did not differ between the phases. Conclusions Itraconazole almost doubles but Grapefruit Juice greatly reduces plasma concentrations of celiprolol. The itraconazole-celiprolol interaction most likely resulted from increased absorption of celiprolol possibly as a result of P-glycoprotein inhibition in the intestine. The reduced celiprolol concentrations during the Grapefruit Juice phase were probably caused by physicochemical factors that interfered with celiprolol absorption, although other mechanisms cannot be excluded. The Grapefruit Juice-celiprolol interaction is probably of clinical relevance. Clinical Pharmacology & Therapeutics (2003) 73, 192–198; doi: 10.1067/mcp.2003.26
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effect of Grapefruit Juice dose on Grapefruit Juice triazolam interaction repeated consumption prolongs triazolam half life
European Journal of Clinical Pharmacology, 2000Co-Authors: Jari J Lilja, Kari T Kivisto, Janne T BackmanAbstract:Objective: Grapefruit Juice inhibits CYP3A4-mediated metabolism of several drugs during first pass. In this study, the effect of Grapefruit Juice dose on the extent of Grapefruit Juice–triazolam interaction was investigated.
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Repeated consumption of Grapefruit Juice considerably increases plasma concentrations of cisapride
Clinical pharmacology and therapeutics, 1999Co-Authors: Kari T Kivisto, Janne T BackmanAbstract:Background Grapefruit Juice increases the bioavailability of several drugs that are metabolized during first pass by CYP3A4. In this study, the effect of Grapefruit Juice on the pharmacokinetics of orally administered cisapride was investigated. Methods In a randomized, two-phase crossover study, 10 healthy volunteers took either 200 mL double-strength Grapefruit Juice or water three times a day for 2 days. On day 3, each subject ingested 10 mg cisapride with either 200 mL Grapefruit Juice or water, and an additional 200 mL was ingested ½ hour and 1½ hours after cisapride administration. Timed blood samples were collected for 32 hours after cisapride intake, and a standard 12-lead ECG was recorded before the administration of cisapride and 2, 5, 8, and 12 hours later. Results The mean peak plasma concentration of cisapride was increased by 81% (range, 38% to 138%; P
Jari J Lilja - One of the best experts on this subject based on the ideXlab platform.
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effects of Grapefruit Juice on the pharmacokinetics of acebutolol
British Journal of Clinical Pharmacology, 2005Co-Authors: Jari J Lilja, Kari RaaskaAbstract:Aims We aimed to investigate effects of Grapefruit Juice on acebutolol pharmacokinetics. Methods In a randomized cross-over study, 10 healthy subjects ingested 200 mL Grapefruit Juice or water three times daily for 3 days and twice on day 4. On day 3, each subject ingested 400 mg acebutolol with Grapefruit Juice or water. The concentrations of acebutolol and its metabolite diacetolol were measured in plasma and urine up to 33 h. Results Grapefruit Juice decreased the peak plasma concentration (Cmax) of acebutolol by 19% from 872 ± 207 ng mL−1 to 706 ± 140 ng mL−1 (95% CI on the difference −306, −26.4; P < 0.05), and the area under the concentration time curve (AUC0−33 h) by 7%, from 4498 ± 939 ng mL−1 h to 4182 ± 915 ng mL−1 h (95% CI −609, −23.0; P < 0.05). The half-life (t1/2) of acebutolol prolonged from 4.0 to 5.1 h (P < 0.05). The time to peak concentration and the amount of acebutolol excreted into urine (Ae) were unchanged. The Cmax, AUC0−33 h, and Ae of diacetolol were decreased by 24% (P < 0.05), 18% (P < 0.05), and 20% (P < 0.01), respectively, by Grapefruit Juice. Conclusion Grapefruit Juice caused a small decrease in the plasma concentrations of acebutolol and diacetolol by interfering with gastrointestinal absorption. The interaction between the Grapefruit Juice and acebutolol is unlikely to be of clinical significance in most of the patients.
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Effects of Grapefruit Juice on the pharmacokinetics of acebutolol
British journal of clinical pharmacology, 2005Co-Authors: Jari J Lilja, Kari RaaskaAbstract:Aims We aimed to investigate effects of Grapefruit Juice on acebutolol pharmacokinetics. Methods In a randomized cross-over study, 10 healthy subjects ingested 200 mL Grapefruit Juice or water three times daily for 3 days and twice on day 4. On day 3, each subject ingested 400 mg acebutolol with Grapefruit Juice or water. The concentrations of acebutolol and its metabolite diacetolol were measured in plasma and urine up to 33 h. Results Grapefruit Juice decreased the peak plasma concentration (Cmax) of acebutolol by 19% from 872 ± 207 ng mL−1 to 706 ± 140 ng mL−1 (95% CI on the difference −306, −26.4; P
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itraconazole increases but Grapefruit Juice greatly decreases plasma concentrations of celiprolol
Clinical Pharmacology & Therapeutics, 2003Co-Authors: Jari J Lilja, Janne T Backman, Jouko Laitila, Harri Luurila, Pertti J NeuvonenAbstract:Objectives Our objective was to evaluate the effects of itraconazole and Grapefruit Juice on the pharmacokinetics of the β-adrenergic receptor-blocking agent celiprolol in healthy volunteers. Methods In a randomized 3-phase crossover study, 12 healthy volunteers took itraconazole 200 mg orally or placebo twice a day or 200 mL Grapefruit Juice 3 times a day for 2 days. On the morning of day 3, 1 hour after ingestion of itraconazole, placebo, or Grapefruit Juice, each subject ingested 100 mg celiprolol with 200 mL of water (placebo and itraconazole phases) or Grapefruit Juice. In addition, 200 mL of water or Grapefruit Juice was ingested 4 and 10 hours after celiprolol intake. The plasma concentrations of celiprolol, itraconazole, and hydroxyitraconazole and the excretion of celiprolol into urine were measured up to 33 hours after dosing. Systolic and diastolic blood pressures and heart rate were recorded with subjects in a sitting position before the administration of celiprolol and 2, 4, 6, and 10 hours later. Results During the itraconazole phase, the mean area under the plasma concentration-time curve from 0 to 33 hours [AUC(0–33)] of celiprolol was 80% greater (P < .05) than in the placebo phase. During the Grapefruit Juice phase, the mean AUC(0–33) and peak plasma concentration values of celiprolol were reduced to about 13% (P < .001) and 5% (P < .001) of the respective placebo phase values. The cumulative excretion into urine of celiprolol was increased by 59% by itraconazole (P < .05) and decreased by 85% by Grapefruit Juice (P < .001). Hemodynamic variables did not differ between the phases. Conclusions Itraconazole almost doubles but Grapefruit Juice greatly reduces plasma concentrations of celiprolol. The itraconazole-celiprolol interaction most likely resulted from increased absorption of celiprolol possibly as a result of P-glycoprotein inhibition in the intestine. The reduced celiprolol concentrations during the Grapefruit Juice phase were probably caused by physicochemical factors that interfered with celiprolol absorption, although other mechanisms cannot be excluded. The Grapefruit Juice-celiprolol interaction is probably of clinical relevance. Clinical Pharmacology & Therapeutics (2003) 73, 192–198; doi: 10.1067/mcp.2003.26
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effect of Grapefruit Juice dose on Grapefruit Juice triazolam interaction repeated consumption prolongs triazolam half life
European Journal of Clinical Pharmacology, 2000Co-Authors: Jari J Lilja, Kari T Kivisto, Janne T BackmanAbstract:Objective: Grapefruit Juice inhibits CYP3A4-mediated metabolism of several drugs during first pass. In this study, the effect of Grapefruit Juice dose on the extent of Grapefruit Juice–triazolam interaction was investigated.
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Duration of effect of Grapefruit Juice on the pharmacokinetics of the CYP3A4 substrate simvastatin
Clinical pharmacology and therapeutics, 2000Co-Authors: Jari J Lilja, Kari T KivistoAbstract:Background Grapefruit Juice is a potent inhibitor of CYP3A4-mediated drug metabolism. We wanted to investigate how long the inhibitory effect of Grapefruit Juice lasts, with the CYP3A4 substrate simvastatin used as a model drug. Methods This crossover study consisted of 5 study days, during which 10 healthy volunteers ingested 40 mg simvastatin with water (control), with “high-dose” Grapefruit Juice (200 mL double-strength Grapefruit Juice three times a day for 3 days), or 1, 3, and 7 days after ingestion of “high-dose” Grapefruit Juice. For safety reasons, the study was performed in three parts to allow simvastatin-free days between the study days. Serum concentrations of simvastatin and simvastatin acid were measured by liquid chromatography–tandem mass spectrometry up to 12 hours. Results When simvastatin was taken with Grapefruit Juice, the mean peak serum concentration (Cmax) and the mean area under the serum concentration-time curve [AUC(0-∞)] of simvastatin were increased 12.0-fold (P < .001) and 13.5-fold (P < .001), respectively, compared with control. When simvastatin was administered 24 hours after ingestion of the last dose of Grapefruit Juice, the Cmax and AUC(0-∞) were increased 2.4-fold (P < .01) and 2.1-fold (P < .001), respectively, compared with control. When simvastatin was given 3 days after ingestion of Grapefruit Juice, the Cmax and AUC(0-∞) were increased 1.5-fold (P = .12) and 1.4-fold (P = .09), respectively, compared with control. Seven days after ingestion of Grapefruit Juice, no differences in the Cmax or AUC(0-∞) of simvastatin were seen. The mean Cmax and AUC(0-∞) of simvastatin acid were increased 5.0-fold and 4.5-fold, respectively (P < .001), compared with control when simvastatin was taken with Grapefruit Juice and 1.7-fold (P < .01) when it was taken 24 hours after ingestion of Grapefruit Juice. After an interval of 3 or 7 days between ingestion of Grapefruit Juice and simvastatin, the pharmacokinetic variables of simvastatin acid did not differ significantly from those in the control phase. Conclusions When simvastatin is taken 24 hours after ingestion of “high-dose” Grapefruit Juice, the effect of Grapefruit Juice on the AUC of simvastatin is only about 10% of the effect observed during concomitant intake of Grapefruit Juice and simvastatin. The interaction potential of even high amounts of Grapefruit Juice with CYP3A4 substrates dissipates within 3 to 7 days after ingestion of the last dose of Grapefruit Juice. (Clin Pharmacol Ther 2000;68:384-90.) Clinical Pharmacology & Therapeutics (2000) 68, 384–390; doi: 10.1067/mcp.2000.110216
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Grapefruit Juice-drug interactions. Commentary. Author's reply
British Journal of Clinical Pharmacology, 2004Co-Authors: David G. Bailey, J. David Spence, J. Malcolm, O. Arnold, Uwe FuhrAbstract:The novel finding that Grapefruit Juice can markedly augment oral drug bioavailability was based on an unexpected observation from an interaction study between the dihydropyridine calcium channel antagonist, felodipine, and ethanol in which Grapefruit Juice was used to mask the taste of the ethanol. Subsequent investigations showed that Grapefruit Juice acted by reducing presystemic felodipine metabolism through selective post-translational down regulation of cytochrome P450 3A4 (CYP3A4) expression in the intestinal wall. Since the duration of effect of Grapefruit Juice can last 24 h, repeated Juice consumption can result in a cumulative increase in felodipine AUC and C max . The high variability of the magnitude of effect among individuals appeared dependent upon inherent differences in enteric CYP3A4 protein expression such that individuals with highest baseline CYP3A4 had the highest proportional increase. At least 20 other drugs have been assessed for an interaction with Grapefruit Juice. Medications with innately low oral bioavailability because of substantial presystemic metabolism mediated by CYP3A4 appear affected by Grapefruit Juice. Clinically relevant interactions seem likely for most dihydropyridines, terfenadine, saquinavir, cyclosporin, midazolam, triazolam and verapamil and may also occur with lovastatin, cisapride and astemizole. The importance of the interaction appears to be influenced by individual patient susceptibility, type and amount of Grapefruit Juice and administration-related factors. Although in vitro findings support the flavonoid, naringin, or the furanocoumarin, 6',7'-dihydroxybergamottin, as being active ingredients, a recent investigation indicated that neither of these substances made a major contribution to Grapefruit Juice-drug interactions in humans.
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Effects of Grapefruit Juice on the pharmacokinetics of sildenafil.
Clinical pharmacology and therapeutics, 2002Co-Authors: Alexander Jetter, Martina Kinzig-schippers, Monika Walchner-bonjean, Ursula Hering, Jürgen B. Bulitta, Philipp Schreiner, F. Sörgel, Uwe FuhrAbstract:Background And Objectives Because of extensive first-pass metabolism, oral bioavailability of sildenafil reaches only 40%. Formation of the primary metabolite, N-desmethylsildenafil, is mainly mediated by the cytochrome P450 enzyme CYP3A4. In this study we investigated the influence of Grapefruit Juice, containing inhibitors of intestinal CYP3A4, on the pharmacokinetics of sildenafil and N-desmethylsildenafil. Methods In a randomized crossover study, 24 healthy white male volunteers received single 50-mg doses of sildenafil. Two doses each of 250 ml Grapefruit Juice or water, respectively, were administered 1 hour before and together with the drug. Plasma concentrations of sildenafil and N-desmethylsildenafil were determined up to 24 hours post dose by use of liquid chromatography–tandem mass spectrometry (limit of quantification, 1 ng/ml). Results Grapefruit Juice changed the area under the sildenafil plasma concentration–time curve from time zero to infinity [AUC(0-∞)] from 620 [1.53] ng/ml • h to 761 [1.58] ng/ml • h (geometric mean with geometric standard deviation), corresponding to a 23% increase (90% confidence interval, 13%-33%). N-Desmethylsildenafil AUC(0-∞) increased by 24% (90% confidence interval, 17%-32%). Maximum plasma concentrations (Cmax) of sildenafil and N-desmethylsildenafil were essentially unchanged. There was a trend toward a prolonged time to reach Cmax during the Grapefruit Juice period (from a median of 0.75 hour to a median of 1.13 hours), corresponding to an increase by 0.25 hour (90% confidence interval, 0–0.63 hour). Interindividual variability was pronounced in both periods. Conclusions Grapefruit Juice increases sildenafil bioavailability and tends to delay sildenafil absorption. Sildenafil pharmacokinetics may become less predictable with Grapefruit Juice. Although patients usually will not be endangered by concomitant use of Grapefruit Juice, it seems advisable to avoid this combination. Clinical Pharmacology & Therapeutics (2002) 71, 21–29; doi: 10.1067/mcp.2002.121236
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Drug Interactions with Grapefruit Juice
Drug Safety, 1998Co-Authors: Uwe FuhrAbstract:Concomitant intake with Grapefruit Juice increases the concentrations of many drugs in humans. The effect seems to be mediated mainly by suppression of the cytochrome P450 enzyme CYP3A4 in the small intestine wall. This results in a diminished first pass metabolism with higher bioavailability and increased maximal plasma concentrations of substrates of this enzyme. The effect was most pronounced in drugs with a high first pass degradation and in many cases has the clear potential to reach clinical relevance, as shown by an occasional change in drug effects or tolerability. For felodipine, nitrendipine, nisoldipine and saquinavir, the interaction was most marked with median increases of area under the curve (AUC) and/or the maximum (peak) plasma drug concentration after singledose administration (C_max) values exceeding 70% of respective control periods. Less pronounced, but possibly relevant, concentration increases were found for nifedipine, nimodipine, verapamil, cyclosporin, midazolam, triazolam and terfenadine. This list is not complete because many drugs have not been studied yet. The components of Grapefruit Juice which are the most probable causes of the interaction are psoralen derivatives, but the flavonoid naringenin may also contribute. Concomitant Grapefruit Juice intake does not generally decrease the variability of drug pharmacokinetic parameters. Therefore, it is recommended that patients refrain from drinking Grapefruit Juice when they are taking a drug that is extensively metabolised, unless a lack of interaction has already been demonstrated for that drug. It is also recommended that drugs possibly interacting with Grapefruit Juice should be appropriately labelled. A place for Grapefruit Juice as a drug-sparing agent in treatment involving expensive medicine cannot be derived from the information currently available on Grapefruit Juice interactions.
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Grapefruit Juice increases oral nimodipine bioavailability.
International journal of clinical pharmacology and therapeutics, 1998Co-Authors: Uwe Fuhr, Maier-brüggemann A, Blume H, Wolfgang Mück, Unger S, Kuhlmann J, Huschka C, Zaigler M, S. RietbrockAbstract:The bioavailability of dihydropyridine calcium channel blockers following oral administration was shown to be increased by concomitant intake of Grapefruit Juice for all drugs of this class tested up to now. Here we report a randomized crossover interaction study on the effects of Grapefruit Juice on the pharmacokinetics of nimodipine and its metabolites. Eight healthy young men (4 smokers/4 nonsmokers) were included. Nimodipine was given as a single 30 mg tablet (Nimotop) with either 250 ml of water or 250 ml of Grapefruit Juice (751 mg naringin/l). Drug concentrations in plasma withdrawn up to 24 hours postdose were measured by GC-ECD, and model-independent pharmacokinetic parameters were estimated. The study was handled as an equivalence problem. Point estimators and ANOVA based 90% confidence intervals (CI) were calculated for the test (= Grapefruit Juice period) to reference (= water period) ratios using dose-normalized concentrations. The absence of a relevant interaction was assumed if the CIs were within the 0.67 - 1.50 range. C max for nimodipine reached 124% of the reference period (90% CI 0.76 - 2.01), AUC was increased to 151% (90% Cl 114% - 200%), respectively. The null hypothesis relevant interaction thus could not be rejected for the primary pharmacokinetic parameters AUC and C max . The ratios of metabolite AUC to parent drug AUC were slightly reduced with Grapefruit Juice intake. Additionally, there was evidence for a more pronounced hemodynamic response in the Grapefruit Juice period. To avoid the interaction, nimodipine should not be taken with Grapefruit Juice.
