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Pertti J. Neuvonen - One of the best experts on this subject based on the ideXlab platform.
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Grapefruit juice inhibits the metabolic activation of clopidogrel.
Clinical pharmacology and therapeutics, 2013Co-Authors: Mikko T. Holmberg, Pertti J. Neuvonen, 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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Effects of Grapefruit juice on the pharmacokinetics of acebutolol
British journal of clinical pharmacology, 2005Co-Authors: Jari J Lilja, Kari Raaska, Pertti J. NeuvonenAbstract: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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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 Backman, Pertti J. NeuvonenAbstract: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 Kivisto, Pertti J. NeuvonenAbstract: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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repeated consumption of Grapefruit juice considerably increases plasma concentrations of cisapride
Clinical Pharmacology & Therapeutics, 1999Co-Authors: Kari T Kivisto, Jari J Lilja, Janne T Backman, Pertti J. NeuvonenAbstract: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 <.01) and the total area under the plasma cisapride concentration–time curve by 144% (range, 65% to 244%; P < .01) by Grapefruit juice. The time of the peak concentration of cisapride was prolonged from 1.5 to 2.5 hours (P < .05) and the elimination half-life from 6.8 to 8.4 hours (P < .05) by Grapefruit juice. ECG tracings did not show any significant differences in the QTc interval between the Grapefruit juice and control phases. Conclusions Grapefruit juice significantly increases plasma concentrations of cisapride, probably by inhibition of the CYP3A4-mediated first-pass metabolism of cisapride in the small intestine. Concomitant use of high amounts of Grapefruit juice and cisapride should be avoided, at least in patients with risk factors for cardiac arrhythmia. Clinical Pharmacology & Therapeutics (1999) 66, 448–453; doi:
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 Raaska, Pertti J. NeuvonenAbstract: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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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 Backman, Pertti J. NeuvonenAbstract: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 Kivisto, Pertti J. NeuvonenAbstract: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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repeated consumption of Grapefruit juice considerably increases plasma concentrations of cisapride
Clinical Pharmacology & Therapeutics, 1999Co-Authors: Kari T Kivisto, Jari J Lilja, Janne T Backman, Pertti J. NeuvonenAbstract: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 <.01) and the total area under the plasma cisapride concentration–time curve by 144% (range, 65% to 244%; P < .01) by Grapefruit juice. The time of the peak concentration of cisapride was prolonged from 1.5 to 2.5 hours (P < .05) and the elimination half-life from 6.8 to 8.4 hours (P < .05) by Grapefruit juice. ECG tracings did not show any significant differences in the QTc interval between the Grapefruit juice and control phases. Conclusions Grapefruit juice significantly increases plasma concentrations of cisapride, probably by inhibition of the CYP3A4-mediated first-pass metabolism of cisapride in the small intestine. Concomitant use of high amounts of Grapefruit juice and cisapride should be avoided, at least in patients with risk factors for cardiac arrhythmia. Clinical Pharmacology & Therapeutics (1999) 66, 448–453; doi:
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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 Kivisto, Pertti J. NeuvonenAbstract: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
Kari T Kivisto - One of the best experts on this subject based on the ideXlab platform.
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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 Backman, Pertti J. NeuvonenAbstract: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 Kivisto, Pertti J. NeuvonenAbstract: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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repeated consumption of Grapefruit juice considerably increases plasma concentrations of cisapride
Clinical Pharmacology & Therapeutics, 1999Co-Authors: Kari T Kivisto, Jari J Lilja, Janne T Backman, Pertti J. NeuvonenAbstract: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 <.01) and the total area under the plasma cisapride concentration–time curve by 144% (range, 65% to 244%; P < .01) by Grapefruit juice. The time of the peak concentration of cisapride was prolonged from 1.5 to 2.5 hours (P < .05) and the elimination half-life from 6.8 to 8.4 hours (P < .05) by Grapefruit juice. ECG tracings did not show any significant differences in the QTc interval between the Grapefruit juice and control phases. Conclusions Grapefruit juice significantly increases plasma concentrations of cisapride, probably by inhibition of the CYP3A4-mediated first-pass metabolism of cisapride in the small intestine. Concomitant use of high amounts of Grapefruit juice and cisapride should be avoided, at least in patients with risk factors for cardiac arrhythmia. Clinical Pharmacology & Therapeutics (1999) 66, 448–453; doi:
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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 Kivisto, Pertti J. NeuvonenAbstract: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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Grapefruit juice greatly increases serum concentrations of lovastatin and lovastatin acid
Clinical Pharmacology & Therapeutics, 1998Co-Authors: Teemu Kantola, Kari T Kivisto, Pertti J. NeuvonenAbstract:Background Grapefruit juice increases the bioavailability of several drugs known to be metabolized by CYP3A4. We wanted to investigate a possible interaction of Grapefruit juice with lovastatin, a cholesterollowering agent that is partially metabolized by CYP3A4. Methods An open, randomized, two-phase crossover study with an interval of 2 weeks between the phases was carried out. Ten healthy volunteers took either 200 ml double-strength Grapefruit juice or water orally three times a day for 2 days. On day 3, each subject ingested 80 mg lovastatin with either 200 ml Grapefruit juice or water, and an additional dose of 200 ml was ingested ½ and ½ hours after lovastatin intake. Serum concentrations of lovastatin and lovastatin acid were measured up to 12 hours. Results Grapefruit juice greatly increased the serum concentrations of both lovastatin and lovastatin acid. The mean peak serum concentration (Cmax) of lovastatin was increased about 12-fold (range, 5.2-fold to 19.7-fold; p < 0.001) and the area under the concentration-time curve [AUC(0–12)] was increased 15-fold (range, 5.7-fold to 26.3-fold; p < 0.001) by Grapefruit juice. The mean Cmax and AUC(0–12) of lovastatin acid were increased about fourfold (range, 1.8-fold to 11.5-fold; p < 0.001) and fivefold (range, 2.4-fold to 23.3-fold; p < 0.001) by Grapefruit juice, respectively. The half-lives of lovastatin and lovastatin acid remained unchanged. Conclusions Grapefruit juice can greatly increase serum concentrations of lovastatin and its active metabolite, lovastatin acid, probably by preventing CYP3A4-mediated first-pass metabolism in the small intestine. The concomitant use of Grapefruit juice with lovastatin and simvastatin should be avoided, or the dose of these 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors should be reduced accordingly. Clinical Pharmacology & Therapeutics (1998) 63, 397–402; doi:
Janne T Backman - One of the best experts on this subject based on the ideXlab platform.
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Grapefruit juice inhibits the metabolic activation of clopidogrel.
Clinical pharmacology and therapeutics, 2013Co-Authors: Mikko T. Holmberg, Pertti J. Neuvonen, 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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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 Backman, Pertti J. NeuvonenAbstract: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 & Therapeutics, 1999Co-Authors: Kari T Kivisto, Jari J Lilja, Janne T Backman, Pertti J. NeuvonenAbstract: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 <.01) and the total area under the plasma cisapride concentration–time curve by 144% (range, 65% to 244%; P < .01) by Grapefruit juice. The time of the peak concentration of cisapride was prolonged from 1.5 to 2.5 hours (P < .05) and the elimination half-life from 6.8 to 8.4 hours (P < .05) by Grapefruit juice. ECG tracings did not show any significant differences in the QTc interval between the Grapefruit juice and control phases. Conclusions Grapefruit juice significantly increases plasma concentrations of cisapride, probably by inhibition of the CYP3A4-mediated first-pass metabolism of cisapride in the small intestine. Concomitant use of high amounts of Grapefruit juice and cisapride should be avoided, at least in patients with risk factors for cardiac arrhythmia. Clinical Pharmacology & Therapeutics (1999) 66, 448–453; doi:
William M. Bennett - One of the best experts on this subject based on the ideXlab platform.
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Interaction Between Cyclosporine and Grapefruit Juice Requires Long‐Term Ingestion in Stable Renal Transplant Recipients
Pharmacotherapy, 1998Co-Authors: Lane J. Brunner, John Vallian, Douglass J. Stennett, Mary M. Meyer, Myrna Y. Munar, Marsha Wolfson, William M. BennettAbstract:Study Objective. To examine the effect of the concurrent administration of increasing amounts of Grapefruit juice, an inhibitor of drug metabolism, on the steady-state pharmacokinetics of cyclosporine. Design. Open-label, three-period crossover, food-drug interaction study in stable renal transplant patients. Setting. A university-affiliated clinical research center. Patients. Sixteen stable renal transplant recipients. Intervention. Cyclosporine was administered with 240 ml of water, 240 ml of Grapefruit juice, or several 240-ml glasses of Grapefruit juice, and serial blood samples were taken to estimate the effect of Grapefruit juice on cyclosporine pharmacokinetics. Measurements and Main Results. Grapefruit juice caused a significant increase in cyclosporine area under the curve, however, no significant effect was seen in other pharmacokinetic parameters. Grapefruit juice caused an increase in the 24-hour trough cyclosporine concentration, which may be of clinical significance if long-term ingestion of Grapefruit juice is recommended. Conclusion. A drug interaction exists between cyclosporine and Grapefruit juice, and it is likely at the level of intestinal drug absorption.
