Effects of daily ingestion of cranberry juice on the pharmacokinetics of warfarin, tizanidine, and midazolam--probes of CYP2C9, CYP1A2, and CYP3A4.

Case reports suggest that cranberry juice can increase the anticoagulant effect of warfarin. We investigated the effects of cranberry juice on R-S-warfarin, tizanidine, and midazolam; probes of CYP2C9, CYP1A2, and CYP3A4. Ten healthy volunteers took 200 ml cranberry juice or water t.i.d. for 10 days. On day 5, they ingested 10 mg racemic R-S-warfarin, 1 mg tizanidine, and 0.5 mg midazolam, with juice or water, followed by monitoring of drug concentrations and thromboplastin time. Cranberry juice did not increase the peak plasma concentration or area under concentration-time curve (AUC) of the probe drugs or their metabolites, but slightly decreased (7%; P=0.051) the AUC of S-warfarin. Cranberry juice did not change the anticoagulant effect of warfarin. Daily ingestion of cranberry juice does not inhibit the activities of CYP2C9, CYP1A2, or CYP3A4. A pharmacokinetic mechanism for the cranberry juice-warfarin interaction seems unlikely.

Effects of orange juice on the pharmacokinetics of atenolol.

OBJECTIVE: Fruit juices can significantly change the pharmacokinetics of several drugs. Our objective was to investigate the effect of orange juice on the pharmacokinetics of the beta-blocking agent atenolol. METHODS: In a randomized cross-over study with two phases and a washout of 2 weeks, ten healthy volunteers took either 200 ml orange juice or water thrice daily for 3 days and twice on the fourth day. On the morning of day 3, each subject ingested 50 mg atenolol with an additional amount of either 200 ml orange juice or water. The plasma concentrations of atenolol and the cumulative excretion of atenolol into urine were measured up to 33 h after its dosing. Systolic and diastolic blood pressures and heart rate were recorded in a sitting position before the intake of atenolol and 2, 4, 6, and 10 h after. RESULTS: Orange juice decreased the mean peak plasma concentration (C(max)) of atenolol by 49% (range 16-59%, P<0.01), and the mean area under the plasma atenolol concentration-time curve (AUC(0-33 h)) by 40% (range 25-55%, P<0.01). The time of the peak concentration (t(max)) and the elimination half-life (t(1/2)) of atenolol remained unchanged by orange juice. The amount of atenolol excreted into urine was decreased by 38% (range 17-60%, P<0.01), but the renal clearance remained unaltered. The average heart rate was slightly higher during the orange juice+atenolol phase than during the water+atenolol phase. CONCLUSIONS: Orange juice moderately interferes with the gastrointestinal absorption of atenolol. This food-drug interaction can be of clinical significance.

Rifampicin reduces plasma concentrations of celiprolol.

OBJECTIVE: The beta-adrenoceptor-blocking agent celiprolol undergoes negligible metabolism, but is a substrate for P-glycoprotein. Our objective was to investigate the effects of rifampicin on the pharmacokinetics of celiprolol in healthy subjects. METHODS: In a randomized cross-over study with two phases and a washout of 4 weeks, ten healthy volunteers received a 5-day pretreatment with rifampicin (600 mg daily) or placebo. On day 6, a single 200-mg dose of celiprolol was administered orally. The plasma concentrations of celiprolol and the excretion of celiprolol into urine were measured up to 33 h after its dosing. Systolic and diastolic blood pressures and heart rate were recorded in a sitting position before the administration of celiprolol and 2, 4, 6, and 10 h later. MDR1 (P-glycoprotein) genotype was assessed with respect to polymorphisms in exon 21 (G2677T/A) and in exon 26 (C3435T). RESULTS: Rifampicin pretreatment reduced the median area under the plasma celiprolol concentration-time curve AUC(0-33 h) to 0.44-fold [90% confidence interval (CI), 0.27-0.86], relative to the placebo. The median peak plasma concentration, the time of peak concentration, and the elimination half-life of celiprolol were not significantly changed by rifampicin. During the rifampicin phase, the median amount of celiprolol excreted into urine was decreased by 47% ( P<0.05) and celiprolol renal clearance increased by 19% ( P<0.05) compared with the placebo phase. There were great inter-individual differences in the extent of rifampicin-celiprolol interaction. However, no association was found between the MDR1 polymorphisms and the degree of interaction between rifampicin and celiprolol. No significant differences were observed in hemodynamic parameters between the phases. CONCLUSION: Rifampicin pretreatment reduces plasma celiprolol concentrations, possibly by induction of the efflux transporter P-glycoprotein, particularly in the intestinal wall, which leads to decreased absorption of celiprolol.

Stereoselective pharmacokinetics of cisapride in healthy volunteers and the effect of repeated administration of grapefruit juice.

AIMS: To determine whether the pharmacokinetics of cisapride and its interaction with grapefruit juice are stereoselective. METHODS: The study was a randomized, two-phase cross over design with a washout period of 2 weeks. Ten healthy volunteers were pretreated with either water or 200 ml double strength grapefruit juice three times a day for 2 days. On the 3rd each subject ingested a single 10 mg dose of rac-cisapride tablet. Double strength grapefruit juice (200 ml) or water was administered during cisapride dosing and 0.5 and 1.5 h thereafter. Blood samples were collected before and for 32 h after cisapride administration. Plasma concentrations of cisapride enantiomers were measured by a chiral h.p.l.c. method. A standard 12-lead ECG was recorded before cisapride administration (baseline) and 2, 5, 8, and 12 h later. RESULTS: This study showed that cisapride pharmacokinetics are stereoselective. In control (water treated) subjects, the mean Cmax (30 +/- 13.6 ng ml-1; P = 0.0008) and AUC(0, infinity) (201 +/- 161 ng ml-1 h; P = 0.029) of (-)-cisapride were significantly higher than the Cmax (10.5 +/- 3.4 ng ml-1) and AUC(0, infinity) (70 +/- 51.5 ng ml-1 h) of (+)-cisapride. There was no marked difference in elimination half-life between (-)-cisapride (4.7 +/- 2.7 h) and (+)-cisapride (4.8 +/- 3 h). Compared with the water treated group, grapefruit juice significantly increased the mean Cmax of (-)-cisapride from 30 +/- 13.6-55.5 +/- 18 ng ml-1 (95% CI on mean difference, -33, -17; P = 0.00005) and of (+)-cisapride from 10.5 +/- 3.4 to 18.4 +/- 6.2 ng ml-1 (95% CI on mean difference, -11.8, -3.9, P = 0.00015). The mean AUC(0, infinity) of (-)-cisapride was increased from 201 +/- 161 to 521.6 +/- 303 ng ml-1 h (95% CI on mean difference, -439, -202; P = 0.0002) and that of (+)-cisapride from 70 +/- 51.5 to 170 +/- 91 ng ml-1 h (95% CI on mean difference, -143, -53; P = 0.0005). The tmax was also significantly increased for both enantiomers (from 1.35 to 2.8 h for (-)-cisapride and from 1.75 to 2.9 h for (+)-cisapride in the control and grapefruit juice group, respectively; P < 0.05). The t(1/2) of (-)-cisapride was significantly increased by grapefruit juice, while this change did not reach significant level for (+)-cisapride. The proportion of pharmacokinetic changes brought about by grapefruit juice was similar for both enantiomers, suggesting non-stereoselective interaction. We found no significant difference in mean QTc intervals between the water and grapefruit juice treated groups. CONCLUSIONS: The pharmacokinetics of cisapride is stereoselective. Grapefruit juice elevates plasma concentrations of both (-)- and (+)-cisapride, probably through inhibition of CYP3A in the intestine. At present, there are no data on whether the enantiomers exhibit stereoselective pharmacodynamic actions. If they do, determination of plasma concentrations of the individual enantiomers as opposed to those of racemic cisapride may better predict the degree of drug interaction, cardiac safety and prokinetic efficacy of cisapride.

Duration of effect of grapefruit juice on the pharmacokinetics of the CYP3A4 substrate simvastatin.

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-infinity)] 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-infinity) 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-infinity) 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-infinity) of simvastatin were seen. The mean Cmax and AUC(0-infinity) 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.

Effect of grapefruit juice dose on grapefruit juice-triazolam interaction: repeated consumption prolongs triazolam half-life.

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. METHODS: In a randomised, four-phase, crossover study, 12 healthy volunteers received 0.25 mg triazolam with water, with 200 ml normal-strength or double-strength grapefruit juice or, on the third day of multiple-dose [three times daily (t.i.d.)] administration of double-strength grapefruit juice. Timed blood samples were collected up to 23 h after dosing, and the effects of triazolam were measured with four psychomotor tests up to 10 h after dosing. RESULTS: The area under the plasma triazolam concentration time curve (AUC(0-infinity)) was increased by 53% (P < 0.01), 49% (P < 0.01) and 143% (P < 0.001) by a single dose of normal-strength, a single dose of double-strength and multiple-dose administration of double-strength grapefruit juice, respectively. The peak plasma concentration (Cmax) of triazolam was increased by about 40% by a single dose of normal-strength grapefruit juice (P < 0.01) and multiple-dose grapefruit juice (P < 0.01) and by 25% by a single dose of double-strength grapefruit juice (P < 0.05). The elimination half-life (t(1/2)) of triazolam was prolonged by 54% during the multiple-dose grapefruit juice phase (P < 0.001). A significant increase in the pharmacodynamic effects of triazolam was seen during the multiple-dose grapefruit juice phase in the digit symbol substitution test (DSST, P < 0.05), in subjective overall drug effect (P < 0.05) and in subjective drowsiness (P < 0.05). CONCLUSIONS: Even one glass of grapefruit juice increases plasma triazolam concentrations, but repeated consumption of grapefruit juice produces a significantly greater increase in triazolam concentrations than one glass of juice. The t(1/2) of triazolam is prolonged by repeated consumption of grapefruit juice, probably due to inhibition of hepatic CYP3A4 activity.

Repeated consumption of grapefruit juice considerably increases plasma concentrations of cisapride.

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 1/2 hour and 1 1/2 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.

Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin.

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 1/2 hour and 1 1/2 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(O-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.

Grapefruit juice-simvastatin interaction: effect on serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors.

BACKGROUND: Simvastatin is a cholesterol-lowering agent that is metabolized through CYP3A4. We studied the effect of grapefruit juice on the pharmacokinetics of orally administered simvastatin. METHODS: In a randomized, 2-phase crossover study, 10 healthy volunteers took either 200 mL double-strength grapefruit juice or water 3 times a day for 2 days. On day 3, each subject ingested 60 mg simvastatin with either 200 mL grapefruit juice or water, and an additional 200 mL was ingested 1/2 and 1 1/2 hours after simvastatin administration. Serum concentrations of simvastatin and simvastatin acid were measured by liquid chromatography-tandem mass spectrometry (LC-MS-MS) and those of active (naive) and total (after hydrolysis) 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors by a radioenzyme inhibition assay. RESULTS: Grapefruit juice increased the mean peak serum concentration (Cmax) of unchanged simvastatin about 9-fold (range, 5.1-fold to 31.4-fold; P < .01) and the mean area under the serum simvastatin concentration-time curve [AUC(0-infinity)] 16-fold (range, 9.0-fold to 37.7-fold; P < .05). The mean Cmax and AUC(0-infinity) of simvastatin acid were both increased about 7-fold (P < .01). Grapefruit juice increased the mean AUC(0-infinity) of active and total HMG-CoA reductase inhibitors 2.4-fold (P < .01) and 3.6-fold (P < .01), respectively. The time of the peak concentration of active and total HMG-CoA reductase inhibitors was increased by grapefruit juice (P < .05). CONCLUSION: Grapefruit juice greatly increased serum concentrations of simvastatin and simvastatin acid and, to a lesser extent, those of active and total HMG-CoA reductase inhibitors. The probable mechanism of this interaction was inhibition of CYP3A4-mediated first-pass metabolism of simvastatin by grapefruit juice in the small intestine. Concomitant use of grapefruit juice and simvastatin, at least in large amounts, should be avoided, or the dose of simvastatin should be greatly reduced.

Grapefruit juice substantially increases plasma concentrations of buspirone.

BACKGROUND: Buspirone has a low oral bioavailability because of extensive first-pass metabolism. The effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of orally administered buspirone is not known. METHODS: In a randomized, 2-phase crossover study, 10 healthy volunteers took either 200 mL double-strength grapefruit juice or water 3 times a day for 2 days. On day 3, each subject ingested 10 mg buspirone with either 200 mL grapefruit juice or water, and an additional 200 mL was ingested 1/2 hour and 1 1/2 hours after buspirone administration. Timed blood samples were collected up to 12 hours after ingestion, and the effects of buspirone were measured with 6 psychomotor tests up to 8 hours after ingestion. RESULTS: Grapefruit juice increased the mean peak plasma concentration of buspirone 4.3-fold (range, 2-fold to 15.6-fold; P < .01) and the mean area under the plasma buspirone concentration-time curve 9.2-fold (range, 3-fold to 20.4-fold; P < .01). The time of the peak concentration (tmax) of buspirone increased from 0.75 to 3 hours (P < .01), and the elimination half-life (t1/2) was slightly increased (P < .01) by grapefruit juice. A significant increase in the pharmacodynamic effects of buspirone by grapefruit juice was seen only in subjective overall drug effect (P < .01). CONCLUSIONS: Grapefruit juice considerably increased plasma buspirone concentrations. The probable mechanism of this interaction is delayed gastric emptying and inhibition of the cytochrome P450 3A4-mediated first-pass metabolism of buspirone caused by grapefruit juice. Concomitant use of buspirone and at least large amounts of grapefruit juice should be avoided.