Dramatic inhibition of amiodarone metabolism induced by grapefruit juice

AIMS: Grapefruit juice increases blood concentrations of many drugs metabolized by CYP3A. Amiodarone is metabolized by CYP3A to N-desethylamiodarone (N-DEA). The aim of this study was to determine amiodarone kinetics when administrated with and without grapefruit juice. METHODS: Eleven healthy adult volunteers took part in a single sequence, repeated-measures design study. Each subject, who had been evaluated 6 months previously for amiodarone pharmacokinetics, was given a single oral dose of amiodarone (17 mg kg-1) with three glasses of 300 ml of grapefruit juice on the same day. RESULTS: Grapefruit juice completely inhibited the production of N-DEA, the major metabolite of amiodarone, in all subjects and increased the area-under-the-curve (AUC) and maximum concentration of amiodarone (Cmax) by 50% and 84%, respectively, as compared with the control period during which water had been administrated instead of grapefruit juice (AUC: 35.9 +/- 14.3 vs 23.9 +/- 11.2 microg ml-1 h, P < 0.005 and Cmax: 3.45 +/- 1.7 vs 1.87 +/- 0.6 microg ml-1, P < 0. 02, respectively) (means +/- s.d.). This inhibition of N-DEA production led to a decrease in the alterations caused by amiodarone on PR and QTc intervals. CONCLUSIONS: Grapefruit juice dramatically alters the metabolism of amiodarone with complete inhibition of N-DEA production. These results are in agreement with in vitro data pointing to the involvement of CYP3 A in the metabolism of amiodarone and suggests that this interaction should be taken into account when prescribing this antiarrhythmic drug.     

Effects of grapefruit juice on the pharmacokinetics of acebutolol

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 (AUC(0-33 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, AUC(0-33 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.     

Influence of grapefruit juice on pharmacokinetics of triptolide in rats grapefruit juice on the effects of triptolide

1.?Triptolide, a major pharmacological component isolated from Tripterygium wilfordii Hook F (TWHF), is a substrate of both CYP3A4 and P-glycoprotein (P-gp).

2.?This study investigates the effects of GFJ on the pharmacokinetics of triptolide in rats.

3.?The pharmacokinetics of orally administered triptolide with or without GFJ pretreatment were investigated. A mechanistic study was also undertaken using the Caco-2 cell transwell model and rat liver microsomes incubation systems to support the in vivo pharmacokinetic data.

4.?The results indicated that coadministration of GFJ could increase the systemic exposure of triptolide significantly, including area under the curve (828.58?±?79.72 versus 541.53?±?45.23?ng·h/mL) and maximum plasma concentration (273.58?±?27.98 versus 193.67?±?10.08?ng/mL). The apparent permeability of triptolide across the Caco-2 cell transwell model increased significantly with the pretreatment of GFJ (from 1.62?±?0.25?×?10^?6 to 2.51?±?0.41?×?10^?6 cm/s), and the metabolic stability of triptolide was also increased from 32.6?±?5.1 to 52.5?±?7.8?min with the pretreatment of GFJ, and the difference was significant (p?5.?In conclusion, GFJ could increase the systemic exposure of triptolide in rats, when GFJ and triptolide was coadministered, and it might work mainly through increasing the absorption of triptolide by inhibiting P-gp, or through slowing down the metabolism of triptolide in rat liver by inhibiting the activity of CYP3A4.     

Effects of regular consumption of grapefruit juice on the pharmacokinetics of simvastatin

AIMS: Simvastatin, a substrate for CYP3A4, is extensively metabolized during the first pass. Our aim was to investigate the effect of regular consumption of grapefruit juice on the pharmacokinetics of simvastatin. METHODS: In a randomized cross-over study with two phases, 10 healthy volunteers ingested grapefruit juice 200 ml or water (control) for 3 days. On day 3, a single 40-mg dose of simvastatin was administered with grapefruit juice 200 ml or water. Plasma concentrations of simvastatin and simvastatin acid were determined up to 24 h. RESULTS: Grapefruit juice increased the area under the plasma concentration-time curves from 0 to 24 h [AUC(0-24)] of simvastatin 3.6-fold (range 1.8-6.0-fold; P < 0.01) and that of simvastatin acid 3.3-fold (range 2.1-5.6-fold; P < 0.01), respectively. The peak concentrations (C(max)) of simvastatin and simvastatin acid were increased 3.9-fold (range 2.3-9.3-fold; P < 0.01) and 4.3-fold (range 2.7-7.9-fold; P < 0.01) by grapefruit juice. CONCLUSIONS: Even one glass of grapefruit juice, taken daily, considerably increases the plasma concentrations of simvastatin and simvastatin acid. Grapefruit juice may increase both the cholesterol-lowering effect and the risk of adverse effects of simvastatin.     

Serum concentrations and clinical effects of atorvastatin in patients taking grapefruit juice daily

AIM

To determine whether customary exposure to grapefruit juice (GFJ) alters serum concentrations, effectiveness, and potential adverse effects of atorvastatin in patients requiring the medication.

METHODS

Patients receiving extended treatment with atorvastatin (10, 20 or 40 mg day⁻¹) at a stable dose received 300 ml day⁻¹ of 100% GFJ for a period of 90 days. One cohort of patients (arm A, n = 60) continued on their current dose of atorvastatin; the second cohort (arm B, n = 70) reduced the daily dose by 50%. Serum atorvastatin, lipid profile, liver functions, and creatine phosphokinase (CPK) were measured at baseline and at 30, 60, and 90 days after starting GFJ.

RESULTS

In Arm A patients, co-ingestion of GFJ significantly elevated serum atorvastatin by 19% to 26% compared with baseline. Changes in lipid profile relative to baseline were negligible. There were no adverse effects on liver function tests or CPK. In arm B patients, serum atorvastatin declined by 12% to 25% compared to baseline, with a small but significant unfavourable effect in serum lipid profile. There were no adverse effects on liver function tests or CPK.

CONCLUSION

In patients on extended stable atorvastatin treatment, addition of daily GFJ in typical quantities slightly elevates serum atorvastatin concentrations, but has no meaningful effect on the serum lipid profile, and causes no detectable adverse liver or muscle effects. Reduction of atorvastatin dosage when moderate amounts of GFJ are co-ingested does not appear to be necessary.     

The metabolism of methaqualone in patients with biliary cirrhosis or secondary carcinoma of the liver

Summary The metabolism of methaqualone has been studied in three patients with secondary carcinoma of the liver and two with biliary cirrhosis. The urinary excretion of fiveC-monohydroxy metabolites and theN-oxide was studies in the 24 h period immediately after oral dosing with 250 mg methaqualone (Melsed). In both patients with biliary cirrhosis and one with primary carcinoma of the bile duct or pancreas with secondaries in the liver the pattern of metabolites was normal. In a patient with oat cell carcinoma with secondaries in the liver some metabolite patterns were disturbed and increased metabolite excretion occurred. A patient with primary carcinoma of the breast with secondaries in the liver gave a completely abnormal metabolite pattern.     

Effects of grapefruit juice on the absorption of levothyroxine

AIMS: Our aim was to study the effect of grapefruit juice on the pharmacokinetics of levothyroxine. METHODS: In a randomized cross-over study with two phases, 10 healthy subjects ingested 200 ml grapefruit juice or water (control) three times daily for 2 days. On day 3, a single 600 microg dose of levothyroxine was administered with 200 ml grapefruit juice or water, which was also ingested 1 h before and 1 h after levothyroxine. Serum concentrations of total thyroxine (T4) and thyroid-stimulating hormone (TSH) were measured up to 24 h. RESULTS: Grapefruit juice decreased slightly (11%; P < 0.01) the maximal increase of T4 concentration after ingestion of levothyroxine from 66.4 nmol l(-1) to 59.4 nmol l(-1) (95% CI on the difference -11.3, -2.7). The incremental areas under the serum T4 concentration-time curve (dAUC) during the first 4 and 6 h were also decreased slightly: dAUC(0,4 h) by 13% (P < 0.05), from 195 nmol l(-1) h to 169 nmol l(-1) h (95% CI -51, -1) and dAUC(0,6 h) by 9% (P = 0.085), from 298 nmol l(-1) h to 271 nmol l(-1) h (95% CI -58, 4). The decrease in the serum concentration of TSH (1.25 mU l(-1)) measured 24 h after ingestion of levothyroxine, was not altered by grapefruit juice. CONCLUSIONS: Grapefruit juice may slightly delay the absorption of levothyroxine, but it seems to have only a minor effect on its bioavailability. Accordingly, the clinical relevance of the grapefruit juice-levothyroxine interaction is likely to be small.     

Effect of grapefruit juice on plasma chloroquine kinetics in mice

1. It is known that grapefruit juice (GFJ) may interact with drugs concomitantly administered by inhibiting first-pass metabolism during the intestinal absorption phase. However, its interaction with chloroquine has not been studied previously. 2. Grapefruit juice (4 mL/kg) was given orally to mice 1 h prior to oral administration of chloroquine (100 mg/kg) and the concentration of the latter drug was measured fluorometrically in the plasma 0, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 18 and 24 h after its administration. 3. The mean (+/-SEM) of area under the curve values after administration of water +/- control) and GFJ were 5.34 +/- 0.38 and 7.01 +/- 0.66 mg.h/L, respectively. The corresponding mean C(max) values were 763.4 +/- 39.1 and 859.2 +/- 45.2 mg/L and the corresponding T(max) values (median) were 2.65 and 2.95 h. 4. The results suggest that GFJ coingestion increased the plasma concentration of chloroquine and altered some kinetic parameters of chloroquine. The clinical significance of this interaction in patients with malaria needs to be investigated.     

Lack of effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of amlodipine

AIMS: To determine whether repeated once daily administration of grapefruit juice altered the pharmacokinetics or pharmacodynamics of the calcium antagonist amlodipine. METHOD:S The effects of grapefruit juice on the pharmacokinetics and pharmacodynamics of oral and intravenous amlodipine were assessed in 20 healthy men in a placebo-controlled, open, randomized, four-way crossover study using single doses of amlodipine 10 mg. For 9 days beginning with the day of administration of amlodipine, grapefruit juice (or water control) was given once daily, and blood samples, blood pressure and heart rate measures were obtained. Plasma concentrations of amlodipine and its enantiomers were determined in separate assays by GC-ECD. RESULTS: Oral amlodipine had high systemic availability (grapefruit juice: 88%; water: 81%). Pharmacokinetic parameters of racemic amlodipine (AUC, Cmax, tmax, and kel) were not markedly changed with grapefruit juice coadministration. Total plasma clearance and volume of distribution, calculated after intravenous amlodipine, were essentially unchanged by grapefruit juice (CL 6.65 ml min-1 kg-1, juice vs 6.93 ml min-1 kg-1, water; Vdss 22.7 l kg-1, juice vs 21.0 l kg-1, water). Grapefruit juice coadministration did not greatly alter the stereoselectivity in amlodipine oral or intravenous kinetics. The sum of S(-) and R(+) enantiomer concentrations correlated well with total racemic amlodipine concentration (r2 = 0. 957; P = 0.0001). Coadministration of grapefruit juice with either route of amlodipine administration did not significantly alter blood pressure changes vs control. CONCLUSIONS: Grapefruit juice has no appreciable effect on amlodipine pharmacodynamics or pharmacokinetics, including its stereoselective kinetics. Bioavailability enhancement by grapefruit juice, noted with other dihydropyridine calcium antagonists, does not occur with amlodipine. Once daily grapefruit juice administration with usual oral doses of amlodipine is unlikely to alter the profile of response in clinical practice.     

Effects of grapefruit juice on the pharmacokinetics of pitavastatin and atorvastatin

AIMS: To compare the effects of grapefruit juice (GFJ) on the pharmacokinetics of pitavastatin and atorvastatin. METHODS: In a randomized, four-phase crossover study, eight healthy subjects consumed either GFJ or water t.i.d. for 4 days in each trial. On each final day, a single dose of 4 mg pitavastatin or 20 mg atorvastatin was administered. RESULTS: GFJ increased the mean AUC(0-24) of atorvastatin acid by 83% (95% CI 23-144%) and that of pitavastatin acid by 13% (-3 to 29%). CONCLUSIONS: Pitavastatin, unlike atorvastatin, appears to be scarcely affected by the CYP3A4-mediated metabolism.     

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.     

Inhibition of cytochrome P450 by furanocoumarins in grapefruit juice and herbal medicines

INTRODUCTIONFuranocoumarins are minor constituents in plants,belonging to Umbelliferae, Rutaceae, Moraceae, andLeguminosae. Some naturally occurring methoxy de-rivatives of furanocoumarins have been applied clinically,coupled with sunbathing, to cure dermatological dis-eases for more than 2000 years, and their confirmedphotosensitizing properties have led to the developmentof a modern medical principle, photochemotherapy[1].On the other hand, some plants containing furano-coumarins are …     

Examining sex-related differences in enteric itraconazole metabolism in healthy adults using grapefruit juice

Objective To explore whether sex-related differences in intestinal itraconazole metabolism exist in healthy adults using grapefruit juice (GFJ) as a selective enteric cytochrome P450 3A4 (CYP3A4) inhibitor. Methods Twenty (ten female) subjects received 240 mL bottled water or single-strength GFJ from a frozen concentrate three times daily for 2 days. On day 3, the subjects received an itraconazole oral solution 200 mg with 240 mL of beverage followed 2 h later by 240 mL of the same beverage. Serial blood sampling for itraconazole and hydroxyitraconazole serum concentrations was performed over a 72-h period. After a 20-day washout, the subjects crossed over and repeated the study. Results Among the female subjects, GFJ reduced itraconazole weight-adjusted apparent oral clearance (Cl/F) (19%, p = 0.006) and increased (30%, p = 0.01), but produced no significant change in hydroxyitraconazole pharmacokinetics. In males, GFJ produced no significant change in either itraconazole, or hydroxyitraconazole pharmacokinetics. Grapefruit juice also significantly reduced the metabolite:parent ratio (12%, p = 0.047), in females, but not males. Itraconazole weight-adjusted oral Cl/F was significantly higher in females than males when itraconazole was administered with water (56%, p = 0.009), and although the extent to which GFJ altered itraconazole weight-adjusted oral CL/F was greater in females, it did not differ significantly between the sexes (p = 0.085). Results The influence of GFJ on the presystemic metabolism of itraconazole was greater in females than males. Repeated ingestion of GFJ significantly reduced itraconazole weight-adjusted oral CL/F and significantly increased exposure in females, but it produced no significant change among males. Although itraconazole weight-adjusted oral Cl/F was much higher in females than in males, the extent to which GFJ altered itraconazole weight-adjusted oral CL/F did not differ significantly between the sexes. This work was presented in part at the American College of Clinical Pharmacy Annual Meeting, October 25, 1999, Kansas City, Missouri and at the 40th Interscience Conference of Antimicrobial Agents and Chemotherapy, September 18, 2000, Toronto Canada.     

Effect of grapefruit juice on the disposition of manidipine enantiomers in healthy subjects

AIM: To examine the effect of grapefruit juice, an inhibitor of CYP3A4 in the small intestine, on the disposition of manidipine enantiomers in healthy subjects. METHODS: A randomized cross-over study with at least a 2-week wash-out period was performed. Seven healthy male volunteers received an oral 40-mg dose of racemic manidipine after an overnight fast with either grapefruit juice (GFJ) or water, as a control study. Plasma concentrations of (S)- and (R)-manidipine were monitored up to 10 h after the dosing. RESULTS: The plasma concentrations of (S)-manidipine were significantly higher (P<0.001) than those of (R)-manidipine in the control phase with an S/R ratio for the AUC0-infinity of 1.62 (95% confidence interval 1.52, 1.73). GFJ significantly increased Cmax and AUC0-infinity of (S)-manidipine by 2.4-fold (P<0.01) and 2.3-fold (P<0.01), respectively, and Cmax and AUC0-infinity of (R)-manidipine were increased by 3.4-fold (P<0.01) and 3.0-fold (P<0.01), respectively. There were significant differences (P<0.01) in GFJ-mediated percentage increases in Cmax and AUC0-infinity of (S)-manidipine compared with those of (R)-manidipine. The S/R ratio for AUC0-infinity was significantly decreased from 1.6 to 1.2 during the GFJ phase (P<0.01). CONCLUSION: These results indicate that the stereoselective disposition of manidipine was altered by GFJ, as an inhibitor of CYP3A4. GFJ appears to affect this metabolic disposal of (R)-manidipine to a greater extent than that of (S)-manidipine.     

Effects of grapefruit juice on pharmacokinetics of atorvastatin and pravastatin in Japanese

AIMS: To investigate the effects of repeated grapefruit juice (GFJ) intake on the pharmacokinetics of atorvastatin and pravastatin in Japanese subjects. METHODS: Two randomized, two-way crossover studies were performed. GFJ or water was given to two groups of 10 subjects each three times daily for 2 days. On the third day, single 10 mg doses of atorvastatin or pravastatin were orally administered with GFJ or water, and an additional 250 ml of GFJ or water was taken before lunch and dinner. Plasma concentrations of atorvastatin and its metabolites were determined over 48 h postdosing and of pravastatin and its metabolites over 24 h postdosing. RESULTS: Compared with in the water group, the AUC(0,48 h) of atorvastatin acid significantly increased by 1.40 fold (95% CI 1.02, 1.92; P < 0.05) when atorvastatin was taken with GFJ. AUC(0,48 h) and C(max) of atorvastatin lactone significantly increased by 1.56 (95% CI 1.33, 1.83; P < 0.001) and 1.29 fold (95% CI 1.09, 1.51; P < 0.01), respectively, when atorvastatin was taken with GFJ. No significant changes were detected in any pravastatin pharmacokinetic parameter examined when pravastatin was taken with GFJ. However, AUC(0,24 h) of pravastatin lactone increased 1.31 fold (95% CI 1.01, 1.71; P < 0.05) with GFJ intake. CONCLUSIONS: GFJ was confirmed to significantly affect the pharmacokinetics of atorvastatin but had little or no effect on those of pravastatin in Japanese subjects.     

Inhibition of the CYP3A4-mediated metabolism and P-glycoprotein-mediated transport of the HIV-1 protease inhibitor saquinavir by grapefruit juice components

AIMS: Cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) are both expressed in the intestinal mucosa and present a barrier to oral drug delivery. CYP3A4 and P-gp share both overlapping tissue distribution and substrate specificity. Grapefruit juice interactions with CYP3A4 substrates are well documented and occur as a consequence of down regulation of intestinal CYP3A4. The aim of the present study was to screen grapefruit juice components against the CYP3A4-mediated metabolism and P-gp mediated transport of the HIV-1 protease inhibitor saquinavir. METHODS: Five grapefruit juice components: quercetin, naringin, naringenin, 6', 7'-dihydroxybergamottin and bergamottin were screened as potential inhibitors of the metabolism of saquinavir by human liver microsomes. The known CYP3A4 inhibitor ketoconazole was also screened for inhibitory potential. These compounds were also screened as modulators of P-gp activity by assessing the directional transport of saquinavir across Caco-2 cell monolayers which express P-gp. The effect of verapamil, a known modulator of P-gp function, was also determined in these cell lines. RESULTS: On preincubation, 6', 7'-dihydroxybergamottin and bergamottin inhibited the metabolism of saquinavir, with IC50 values of 0.33+/-0.23 muM and 0.74+/-0.13 muM, respectively (n=3). Ketoconazole achieved an IC50 of 0. 55+/-0.12 muM (n=4). The other compounds studied failed to reach IC50 at concentrations of up to 100 muM. The transport of saquinavir in the basolateral-->apical (BL-->AP) direction exceeded that in the apical -->basolateral direction (AP-->BL), with apparent permeability coefficients of 199.2+/-15.8x10-7 cm s-1 and 8.00+/-1. 13x10-7 cm s-1, respectively (n=3) which is indicative of a polarized efflux mechanism. The ratio of BL-->AP/AP-->BL for saquinavir was 25, but in the presence of verapamil and ketoconazole this ratio was reduced to 3.6 and 4.0, respectively (n=3), indicating extensive inhibition of P-gp mediated saquinavir efflux. Of the grapefruit juice components studied only naringin and 6', 7'-dihydroxybergamottin had any appreciable effect, reducing the ratio to 7.6 and 7.1, respectively (n=3); but this was due solely to increased AP-->BL transport. CONCLUSIONS: Grapefruit juice components inhibit CYP3A4-mediated saquinavir metabolism and also modulate, to a limited extent, P-gp mediated saquinavir transport in Caco-2 cell monolayers. The in vivo effects of grapefruit juice coadministration are most likely the result of effects on CYP3A4 (inhibition and down regulation) and only to a minor extent on modulation of P-gp function.     

Prediction of the extent and variation of grapefruit juice–drug interactions from the pharmacokinetic profile in the absence of grapefruit juice

The aim of this study was to develop a method for predicting the extent of grapefruit juice (GFJ)–drug interactions and their interindividual variations from the pharmacokinetic profile in the absence of GFJ. The pharmacokinetic profiles of 13 drugs after intravenous and oral administration were used to develop and validate the method. For each drug, the proportion absorbed into the intestine and the intestinal availability (F_g) were calculated from clinical data taken from the literature. Then, the AUC ratio (the ratio of the AUC with GFJ to that without GFJ) was predicted by assuming that F_g was 1.0 when GFJ was concomitantly ingested. According to the developed method, the AUC ratio of felodipine was 2.50 and its coefficient of variation (CV) was 45%, which agreed well with the observed AUC ratio of 2.48 and CV of 51%. Although the developed method overestimated the AUC ratios of some drugs such as nisoldipine, no underestimation occurred. The predicted CV values were consistent with those observed. The developed method might be useful to predict the AUC ratio, along with its interindividual variation, from the pharmacokinetic profile in the absence of grapefruit juice. Copyright © 2014 John Wiley & Sons, Ltd.     

Major determinant factors of the extent of interaction between grapefruit juice and calcium channel antagonists

AIM: To evaluate quantitatively the influence of bioavailability and plasma unbound fraction (f(u)) on the extent of interaction between grapefruit juice (GFJ) and calcium antagonists. METHODS: The extent of drug-GFJ interaction was evaluated from reported clinical interaction studies of 11 calcium antagonists. The relationship between extent of interaction and bioavailability or f(u) was analysed. RESULTS: The following significant hyperbolic relationships were observed: [Extent] = 12.2/[bioavailability] + 1 and [Extent] = 0.718/[f(u)] + 1. CONCLUSIONS: Bioavailability and f(u) are major determinant factors of calcium antagonist-GFJ interaction: a drug with smaller bioavailability or lower f(u) is likely to exhibit a more potent interaction, and vice versa.     

Grapefruit Juice and its Constituents Augment Colchicine Intestinal Absorption: Potential Hazardous Interaction and the Role of P-Glycoprotein

Purpose  To investigate the potential interaction between grapefruit juice (GFJ) and the oral microtubule polymerization inhibitor colchicine, a P-gp and CYP3A4 substrate. Methods  Colchicine intestinal epithelial transport was investigated across Caco-2 cell monolayers in both AP–BL and BL–AP directions, in the absence/presence of known P-gp inhibitors (verapamil and quinidine). The concentration-dependent effects of GFJ and its major constituents (6′-7′-dihydroxybergamottin, naringin and naringenin) on colchicine Caco-2 mucosal secretion were examined. The effect of GFJ on colchicine intestinal-permeability was then investigated in-situ in the rat perfusion model, in both jejunum and ileum. Results  Colchicine exhibited 20-fold higher BL–AP than AP–BL Caco-2 permeability, indicative of net mucosal secretion, which was reduced by verapamil/quinidine. Colchicine AP–BL permeability was increased and BL–AP was decreased by GFJ in a concentration-dependent manner (IC₅₀ values of 0.75% and 0.46% respectively), suggesting inhibition of efflux transport, rather than metabolizing enzyme. Similar effects obtained following pre-experiment incubation with GFJ, even though the juice was not present throughout the transepithelial study. 6′-7′-Dihydroxybergamottin, naringin and naringenin displayed concentration-dependent inhibition on colchicine BL–AP secretion (IC₅₀ values of 90, 592 and 11.6 μM respectively). Ten percent GFJ doubled colchicine rat in-situ ileal permeability, and increased 1.5-fold jejunal permeability. Conclusion  The data suggest that GFJ may augment colchicine oral bioavailability. Due to colchicine narrow therapeutic-index and severely toxic side-effects, awareness of this interaction is prudent.