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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Aliskiren is an antihypertensive drug with a low oral bioavailability.
• Aliskiren is eliminated primarily unchanged into bile, and it is a substrate of the organic anion transporting polypeptide 2B1 (OATP2B1) influx transporter, the P-glycoprotein efflux transporter and cytochrome P450 3A4.
• Flavonoids in orange and apple juice have been shown to inhibit OATP2B1 in vitro.
• Orange juice and apple juice markedly reduce the plasma concentrations of aliskiren probably by inhibiting its OATP2B1-mediated intestinal absorption.
• Concomitant intake of aliskiren with orange or apple juice is best avoided.
AIM The aim of this study was to investigate the effects of orange juice and apple juice on the pharmacokinetics and pharmacodynamics of aliskiren.
METHODS In a randomized crossover study, 12 healthy volunteers ingested 200 ml of orange juice, apple juice or water three times daily for 5 days. On day 3, they ingested a single 150-mg dose of aliskiren. Plasma aliskiren concentrations were measured up to 72 h, its excretion into urine up to 12 h and plasma renin activity up to 24 h.
RESULTS Orange and apple juice reduced aliskiren peak plasma concentrations by 80% (95% CI 63%, 89%, P < 0.001) and 84% (95% CI 72%, 91%, P < 0.001), and the area under the plasma aliskiren concentration–time curve (AUC) by 62% (95% CI 47%, 72%, P < 0.001) and 63% (95% CI 46%, 74%, P < 0.001), respectively, but had no significant effect on its elimination half-life or renal clearance. The decreases in aliskiren AUC by orange and apple juice correlated with aliskiren AUC during the water phase (r= 0.98, P < 0.001). Plasma renin activity was 87% and 67% higher at 24 h after aliskiren during the orange juice and apple juice phases, respectively, than during the water phase (P < 0.05).
CONCLUSIONS Orange juice and apple juice greatly reduce the plasma concentrations and renin-inhibiting effect of aliskiren, probably by inhibiting its OATP2B1-mediated influx in the small intestine. Concomitant intake of aliskiren with orange or apple juice is best avoided.
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Fruit juices are of interest as possible causes of food–drug interactions [1, 2]. Grapefruit juice is known to enhance the oral bioavailability of many cytochrome P-450 (CYP) 3A4 substrates by inactivating intestinal CYP3A4 [1, 3, 4]. Orange and apple juice, in contrast, have not been reported to affect CYP3A4 activity [3, 5, 6]. On the other hand, grapefruit, orange and/or apple juice have decreased the oral bioavailabilities of some drugs, such as fexofenadine, celiprolol, talinolol, atenolol and ciprofloxacin [2, 7–12]. These drugs are all substrates of either organic anion transporting polypeptide 1A2 (OATP1A2) or OATP2B1, or both [7, 13–19]. OATP1A2 and OATP2B1 are influx transporters expressed in the luminal membrane of small intestinal enterocytes [16, 20–22], potentially participating in the active absorption of drugs . Certain constituents of grapefruit, orange and apple juice have been found to inhibit OATP1A2 and OATP2B1 in vitro[7, 23, 24].
Recently, grapefruit juice was found to reduce markedly the peak plasma concentration (Cmax) and the area under the plasma concentration–time curve (AUC) of the renin-inhibiting antihypertensive drug aliskiren . Aliskiren is a substrate of OATP2B1, P-glycoprotein and CYP3A4 [26, 27], and the mechanism of this interaction may be inhibition of the OATP2B1-mediated influx of aliskiren in the small intestine by grapefruit juice. Aliskiren is a hydrophilic, poorly absorbed compound with a low oral bioavailability (2–3%) [26, 28, 29]. It is eliminated mainly by biliary and, to a smaller extent, by renal excretion, with only a small amount being metabolized by CYP3A4 . These characteristics render it susceptible to transporter-mediated drug interactions and a good candidate for a probe substrate for transporters in vivo. In addition to the effects of grapefruit juice, aliskiren has also been found to be susceptible to induction and inhibition of the P-glycoprotein efflux transporter by rifampicin and itraconazole, respectively [30, 31].
Orange and apple juice are widely consumed, but there are only a few studies investigating their possible effects on the pharmacokinetics of drugs in vivo in humans . Because the constituents of these juices inhibit OATP2B1 in vitro, we thought it important to study the effects of these juices on aliskiren. Accordingly, we have investigated the effects of orange juice and apple juice on the pharmacokinetics and pharmacodynamics of aliskiren in a randomized crossover study in healthy volunteers.
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The consumption of either normal-strength orange juice or normal-strength apple juice three times daily greatly reduced the plasma concentrations of aliskiren (Figure 1, Table 1). Orange juice reduced aliskiren Cmax by 80% (the effect on Cmax ranged from a 95% decrease to a 24% increase, P < 0.001), AUC(0–∞) by 62% (range 9–87%, P < 0.001) and Ae by 67% (range 32–87%, P < 0.001; Figure 2). Apple juice reduced aliskiren Cmax by 84% (range, 2–96%, P < 0.001), AUC(0–∞) by 63% (range, 13–87%, P < 0.001) and Ae by 69% (range 14–87%, P < 0.001; Figure 2). Neither orange juice nor apple juice affected the tmax, t1/2 or CLR of aliskiren.
Figure 1. Geometric mean plasma concentrations of aliskiren in 12 healthy volunteers during orange juice (○), apple juice (▵) and water (●) phases. The volunteers ingested 200 ml of orange juice, apple juice or water three times a day for 5 days, and a single 150-mg dose of aliskiren on day 3, together with the first orange juice, apple juice or water dose of the day. Inset depicts the same data on a semi-logarithmic scale. Error bars have been omitted for clarity
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Table 1. Pharmacokinetic variables of a single 150-mg oral dose of aliskiren in 12 healthy volunteers during orange juice, apple juice and water phases
|Variable||Water phase (control)||Orange juice phase||Geometric mean ratio (orange juice/water; 95% CI)||Apple juice phase||Geometric mean ratio (apple juice/water; 95% CI)|
|Aliskiren|| || || || || |
| Cmax (ng ml−1)||110 (67, 182)||22 (12, 40)*||0.20 (0.11, 0.37)||18 (11, 28)*||0.16 (0.09, 0.28)|
| tmax (h)||0.5 (0.5–5)||1 (0.5–5)|| ||1 (0.5–2)|| |
| t1/2 (h)||28 (27, 31)||28 (25, 30)||0.97 (0.86, 1.09)||26 (24, 29)||0.92 (0.83, 1.02)|
| AUC(0–72 h; ng ml−1 h−1)||441 (276, 704)||162 (122, 216)*||0.37 (0.27, 0.51)||161 (126, 207)*||0.37 (0.25, 0.53)|
| AUC(0–∞; ng ml−1 h−1)||481 (302, 767)||183 (138, 243)*||0.38 (0.28, 0.53)||180 (142, 229)*||0.37 (0.26, 0.54)|
| Ae (mg)||0.405 (0.281, 0.582)||0.132 (0.110, 0.158)*||0.33 (0.24, 0.44)||0.127 (0.102, 0.157)*||0.31 (0.22, 0.45)|
| CLR (l h−1)||1.34 (1.07, 1.66)||1.54 (1.32, 1.81)||1.16 (0.97, 1.38)||1.47 (1.24, 1.75)||1.10 (0.89, 1.37)|
Figure 2. Individual Cmax (A) and AUC (B) values of aliskiren in 12 healthy volunteers during orange juice, apple juice and water phases. The numbers refer to the participant numbers in Table 2. The volunteers ingested 200 ml of orange juice, apple juice or water three times a day for 5 days, and a single 150-mg dose of aliskiren on day 3, together with the first orange juice, apple juice or water dose of the day. AUC, area under the plasma concentration–time curve; Cmax, peak plasma concentration
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Aliskiren AUC(0–∞) values varied 7.9-fold, 4.0-fold and 4.2-fold between individual participants during the water, orange juice and apple juice phases, respectively. The changes in aliskiren AUC(0–∞) by orange juice and apple juice correlated with each other and with the AUC(0–∞) of aliskiren during the water phase (r= 0.98, P < 0.001 for all pairs; Figure 3). The SLCO2B1 genotypes of the participants are shown in Table 2. No obvious differences were seen in the pharmacokinetics of aliskiren between participants with different SLCO2B1 genotypes, but the number of individuals with different genotypes was too small to draw any conclusions (Figure 2).
Figure 3. Change in aliskiren AUC by orange juice (○) and apple juice (▵) plotted against aliskiren AUC during the water phase. The volunteers ingested 200 ml of orange juice, apple juice or water three times a day for 5 days, and a single 150-mg dose of aliskiren on day 3, together with the first orange juice, apple juice or water dose of the day. AUC, area under the plasma concentration–time curve
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Table 2. SLCO2B1 genotypes of the healthy volunteers
|Participant||g.-282G > A||c.601G > A||c.935G > A||c.1457C > T|
Plasma renin activity at 4 and 24 h after aliskiren administration was 63% (P= 0.023) and 87% (P= 0.037) higher, respectively, during the orange juice phase than during the water phase (Figure 4, Table 3). During the apple juice phase, plasma renin activity was 67% higher at 24 h after aliskiren than during the water phase (P= 0.036). During the water phase, the plasma aliskiren concentration at 24 h correlated significantly with the plasma renin activity at 24 h (r=−0.615, P= 0.033). Moreover, the relative change in plasma aliskiren concentration at 24 h by orange juice or apple juice correlated with the corresponding relative change in plasma renin activity (orange juice r=−0.580, P= 0.048; apple juice r=−0.716, P= 0.009). No significant differences existed in the systolic or diastolic blood pressure or the heart rate between the phases.
Figure 4. Box-and-whisker plots of plasma renin activity in 12 healthy volunteers 0, 4 and 24 h after a single 150-mg oral dose of aliskiren during orange juice, apple juice and water phases. The volunteers ingested 200 ml of orange juice, apple juice or water three times a day for 5 days, and a single 150-mg dose of aliskiren on day 3, together with the first orange juice, apple juice or water dose of the day. The horizontal lines inside the boxes represent the median, the box edges show the lower and upper quartiles, and the whiskers show the 5th and 95th percentiles. Individual data points are shown as ● (water phase), ○ (orange juice phase) or ▵ (apple juice phase)
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Table 3. Pharmacodynamic variables of a single 150-mg oral dose of aliskiren in 12 healthy volunteers during orange juice, apple juice and water phases
|Variable||Water phase (control)||Orange juice phase||Geometric mean ratio (orange juice/water) (95% CI)||Apple juice phase||Geometric mean ratio (apple juice/water) (95% CI)|
|Plasma renin activity (ng ml−1 h−1)|| || || || || |
| At baseline||0.88 (0.60, 1.28)||0.93 (0.66, 1.33)||1.06 (0.61, 1.84)||0.88 (0.61, 1.27)||1.00 (0.66, 1.51)|
| At 4 h||0.10 (0.10, 0.10)||0.16 (0.11, 0.25)*||1.63 (1.09, 2.45)||0.12 (0.09, 0.17)||1.23 (0.90, 1.68)|
| At 24 h||0.35 (0.19, 0.62)||0.65 (0.45, 0.94)†||1.87 (1.05, 3.35)||0.58 (0.37, 0.90)‡||1.67 (1.04, 2.67)|
|Systolic blood pressure (mmHg)|| || || || || |
| Baseline||127 (117, 137)||122 (113, 132)||0.96 (0.91, 1.02)||123 (115, 132)||0.97 (0.94, 1.00)|
| Average0–24 h||125 (116, 135)||125 (116, 134)||1.00 (0.96, 1.03)||123 (110, 137)||0.98 (0.93, 1.03)|
| Average0–24 h/baseline||0.99 (0.96, 1.01)||1.02 (0.98, 1.07)||1.04 (0.98, 1.09)||1.00 (0.93, 1.07)||1.01 (0.94, 1.09)|
|Diastolic blood pressure (mmHg)|| || || || || |
| Baseline||74 (71, 78)||75 (69, 82)||1.01 (0.95, 1.07)||72 (67, 77)||0.96 (0.91, 1.01)|
| Average0–24 h||73 (68, 79)||73 (68, 77)||0.99 (0.95, 1.03)||71 (64, 78)||0.97 (0.92, 1.02)|
| Average0–24 h/baseline||0.99 (0.95, 1.02)||0.97 (0.93, 1.01)||0.98 (0.93, 1.04)||0.99 (0.91, 1.08)||1.01 (0.94, 1.07)|
|Heart rate (beats min−1)|| || || || || |
| Baseline||63 (57, 70)||60 (53, 69)||0.96 (0.84, 1.11)||62 (55, 70)||0.99 (0.88, 1.10)|
| Average0–24 h||66 (61, 72)||66 (61, 71)||1.00 (0.96, 1.04)||65 (60, 69)||0.98 (0.91, 1.04)|
| Average0–24 h/baseline||1.06 (0.96, 1.16)||1.09 (1.00, 1.20)||1.04 (0.91, 1.18)||1.04 (0.94, 1.16)||0.99 (0.87, 1.12)|
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These data show that regular consumption of orange juice or apple juice can markedly reduce the plasma concentrations of the OATP2B1 substrate aliskiren. Because the Cmax, AUC and Ae of aliskiren were decreased, but the t1/2 and CLR remained unaffected, it is evident that orange juice and apple juice reduced the oral bioavailability of aliskiren. In line with the effects of orange and apple juice on aliskiren pharmacokinetics, the pharmacodynamic response to aliskiren was attenuated by these fruit juices.
The AUC of aliskiren showed about eightfold interindividual variation during the water phase (control), but only fourfold variability during the orange juice and apple juice phases. Moreover, the effects of orange and apple juices on aliskiren AUC varied greatly between individuals, with the largest effects seen in those individuals with the highest aliskiren exposures during the water phase. Interestingly, at the individual level, orange juice and apple juice produced very similar reductions in aliskiren AUC (Figure 3), suggesting that they interact with aliskiren via the same mechanism.
The effect of grapefruit juice on CYP3A4 is well established, but the effects of fruit juices on intestinal transporters are less extensively characterized. Grapefruit, orange and apple juice have reduced the Cmax of fexofenadine, a substrate of OATP1A2 and possibly of OATP2B1 [7, 13, 14, 16, 19], by 62%, 67% and 72%, and its AUC by 63%, 69% and 73%, respectively . Grapefruit juice and orange juice have also decreased the Cmax of celiprolol, a substrate of OATP1A2 , by 95% and 89% and its AUC by 87% and 83%, respectively [9, 10]. In addition, orange juice has reduced the Cmax of the OATP1A2 substrates, atenolol and ciprofloxacin, by 49% and 23% and their AUC values by 40% and 22% [8, 11, 15, 17]. In the present study, orange juice and apple juice were roughly equipotent in reducing the absorption of aliskiren from the gut lumen. Interestingly, the effects of orange and apple juice on aliskiren pharmacokinetics were also of a similar magnitude to those of grapefruit juice (81% decrease in Cmax and 61% decrease in AUC) . As aliskiren is a substrate of OATP2B1, with a Km of 72 µmol L−1, the most likely mechanism of these interactions is inhibition of the OATP2B1-mediated intestinal uptake of aliskiren by orange juice and apple juice.
The duration of the inhibitory effect of grapefruit juice on intestinal OATP transporters seems to be much shorter than that on CYP3A4 . In a previous study, ingestion of grapefruit juice concomitantly with or 2 h before fexofenadine decreased the AUC of fexofenadine by 52% and 38%, respectively, but grapefruit juice ingested 4 h before the drug had no effect . In another study, ingestion of a single 300-ml dose of grapefruit juice concomitantly with talinolol decreased the AUC of talinolol to a similar extent as ingestion of 300 ml of grapefruit juice three times daily for 6 days, prior to talinolol administration . It is likely that the inhibitory effect of orange juice and apple juice on OATP2B1 is of similar duration. Thus, it is possible that ingestion of only a single 200-ml dose of orange juice or apple juice concomitantly or a few hours before aliskiren would decrease the AUC of aliskiren to an extent similar to that seen in the present study with ingestion of 200 ml of these juices three times daily.
Several constituents of fruit juices have been screened for inhibitory activity on intestinal OATP transporters. It should be noted that the contents of juices may vary depending on fruit species and juice brands. In addition, the flavonoids in these juices are usually found as glycoside conjugates that require hydrolysis to active aglycones in vivo, making the in vitro–in vivo prediction of the interactions challenging [33, 34]. The major flavonoid in orange juice, hesperidin, inhibits OATP1A2 in vitro with an IC50 of 2.7 µmol L−1 for fexofenadine uptake , which is much lower than the concentration normally occurring in orange juice (106–1965 µmol L−1) [36–38]. There are no published studies on the possible effects of hesperidin on OATP2B1. However, tangeritin and nobiletin, also found in orange juice (at concentrations of 0.35–1.6 µmol L−1 and 2.5–11 µmol L−1, respectively) [39, 40], have been shown to inhibit the OATP2B1-mediated uptake of estrone-3-sulfate in HEK293 cells at 1 µmol L−1 concentration . The flavonoid constituents of apple juice include phlorizin (6–450 µmol L−1), epicatechin (41 µmol L−1), quercetin (4–23 µmol L−1) and kaempferol (0.5 µmol L−1) [37, 41, 42], of which quercetin and kaempferol have been found to inhibit the OATP2B1-mediated uptake of bromosulphophthalein in HEK293 cells with inhibition constants of 8.7 µmol L−1 and 15.1 µmol L−1, respectively . Moreover, extracts of green tea, containing catechin and epicatechin, and ginkgo leaf, containing kaempferol and quercetin, have been found to inhibit OATP2B1 in vitro. In addition, certain constituents of orange juice, e.g. 3,3',4',5,6,7,8-heptamethoxyflavone, tangeritin and nobiletin, have been shown to inhibit P-glycoprotein in vitro[44–46]. However, inhibition of the P-glycoprotein should increase, not decrease, the plasma concentrations of aliskiren . Therefore, it appears unlikely that inhibition of the P-glycoprotein would play an important role in the interaction between orange juice and aliskiren. Apple juice (up to 5% of normal strength), on the other hand, has had no effect on P-glycoprotein activity in vitro.
The interactions of fruit juices with aliskiren might also be explained by other mechanisms, such as formation of insoluble complexes between fruit juice constituents and aliskiren. In addition, alteration of intestinal pH by organic acids might slightly increase the ionization of basic aliskiren (pKa 9.49) and thus decrease its already low passive permeability [26, 28, 29]. On the other hand, the transport activity of OATP2B1 has been found to be enhanced at acidic pH at least for some substrates . Moreover, increase in intestinal fluid volume by an osmotic effect might decrease intestinal aliskiren concentration and thus slow its absorption. Furthermore, the carbohydrates of fruit juices might delay gastric emptying and therefore delay drug absorption. However, this mechanism seems unlikely, because the tmax of aliskiren was not extended. Grapefruit juice, orange juice and apple juice are all relatively acidic, with pH values of 3.3, 3.8 and 3.6, respectively, for the brands used in our previous grapefruit juice and aliskiren study  and the present study. The main organic acid in grapefruit juice and orange juice is citric acid, but both juices also contain traces of succinic and malic acids . Apple juice contains mainly malic acid, but also lactic and citric acids . Citric acid and lactic acid have not inhibited OATP2B1 at 10 mmol L−1 concentration , but it is not known whether malic acid or succinic acid inhibits OATP2B1. The carbohydrates sucrose, fructose and glucose are the main osmotic components of fruit juices, with grapefruit, orange and apple juice containing about 8 g, 9 g and 10 g of carbohydrates, respectively, per 100 g of juice in the brands used. Further studies are required to clarify the exact mechanisms of the pharmacokinetic interactions between fruit juices and aliskiren.
Because orange juice and apple juice markedly reduced the plasma concentrations of aliskiren and reduced its effect on plasma renin activity, it is possible that ingestion of aliskiren continuously with either of these juices may reduce the antihypertensive efficacy of aliskiren, at least in some patients. In the present study, no differences in haemodynamic effects were observed between the phases after a single dose of aliskiren in healthy volunteers. This can be explained by the delayed start of the blood pressure-lowering effect of aliskiren, which gradually reaches its maximum after 2 weeks of treatment [48, 49]. Marked interindividual variability existed in these interactions, even among this homogenous group of healthy volunteers. The variability is probably even larger among patients using aliskiren. Interestingly, a high-fat meal also reduces the AUC of aliskiren by about 70% . To minimize intraindividual variability in aliskiren exposure because of the food effect, aliskiren is recommended to be taken in a routine pattern with regard to meals [48, 49].
In conclusion, both orange juice and apple juice markedly reduce the plasma concentrations and renin-inhibiting effect of aliskiren, probably by reducing its absorption from the gastrointestinal tract. The interactions may be caused by inhibition of the OATP2B1-mediated intestinal absorption of aliskiren by constituents of these juices, but further studies are required to clarify the mechanisms involved.