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Grapefruit juice greatly reduces the plasma concentrations of the oatp2b1 and cyp3a4 substrate aliskiren

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Grapefruit Juice Greatly Reduces the plasma Concentrations of the OAtp2B1 and CYp3A4 substrate Aliskiren
T Tapaninen1, PJ Neuvonen1 and M Niemi1
In a randomized crossover study, 11 healthy volunteers administered fexofenadine, a substrate of OATP1A2 and pos-
ingested 200 ml of grapefruit juice or water three times a day sibly of OATP2B1.7,21,23,24 Because aliskiren is a substrate, and
for 5 days. On day 3, they ingested a single 150-mg dose of grapefruit juice an inhibitor of both CYP3A4 and OATP2B1,
aliskiren. Grapefruit juice reduced aliskiren peak plasma it is difficult to predict the possible effects of grapefruit juice
concentration (Cmax) by 81% (range, 42–91%, P < 0.001), on aliskiren pharmacokinetics. Therefore, we investigated the
area under the plasma aliskiren concentration–time curve effects of grapefruit juice on the pharmacokinetics of aliskiren.
(AUC)0–∞ by 61% (range, 15–72%, P < 0.001), and elimination
half-life (t½) from 26.1 to 23.6 h (P = 0.020). Therefore, Results
concomitant use of aliskiren and grapefruit juice is best The intake of normal-strength grapefruit juice three times a
avoided.
day markedly reduced the plasma concentrations of aliskiren anThe peak plasma concentration (Cmax) Aliskiren is a renin-inhibiting antihypertensive drug.1,2 When of aliskiren was reduced by 81% (range, 42–91%, P < 0.001), orally administered, it has a bioavailability of only 2–3%, prob- the area under the plasma aliskiren concentration–time curve ably due in large part to poor absorption.2,3 Because aliskiren (AUC)0–∞ by 61% (range, 15–72%, P < 0.001), and the amount of is highly soluble in water and has a low permeability through aliskiren excreted into urine from 0 to 12 h (Ae) by 66% (range, lipid membranes,1,2,4 influx transporters may be important 6–81%, P < 0.001) The Cmax of aliskiren occurred at determinants of its absorption.5 Aliskiren is a substrate of two a later time point during the grapefruit-juice phase (median, transporters expressed in the luminal membrane of small intes- 1 h) than during the water phase (median, 0.5 h) (P = 0.016). The tinal enterocytes: the organic anion–transporting polypeptide intake of grapefruit juice shortened the elimination half-life (t½) 2B1 (OATP2B1) influx transporter and the P-glycoprotein efflux of aliskiren from 26.1 to 23.6 h (P = 0.020). Grapefruit juice had transporter.4,6–8 Aliskiren is eliminated primarily via excretion of no significant effect on the renal clearance (CLR) of aliskiren, the unchanged drug into the bile and, to a smal er extent, excre- and there was no significant difference in plasma renin activity tion into urine and oxidative biotransformation through cyto- between the grapefruit-juice and water phases.
chrome P450 3A4 (CYP3A4).3 The hepatic uptake of aliskiren is probably mediated by OATP2B1, and biliary excretion by Discussion
P-glycoprotein.4,7–9 Itraconazole, an inhibitor of CYP3A4 and These data show that grapefruit juice can have a profound effect P-glycoprotein,10–13 and cyclosporine, an inhibitor of CYP3A4, on the pharmacokinetics of aliskiren, a substrate of OATP2B1 P-glycoprotein, and OATP2B1,13–16 have been shown to mark- and CYP3A4.3,4 Three glasses a day of normal-strength grape- edly increase the systemic exposure to aliskiren.17,18 fruit juice markedly decreased the Cmax, AUC, and Ae of Grapefruit juice is a mechanism-based inhibitor of intesti- aliskiren, consistent with a reduction in the bioavailability of the nal CYP3A4 and enhances the oral bioavailability of many orally administered drug. The most likely mechanism of inter- CYP3A4 substrates, as shown, for example, in the pioneering action is that grapefruit juice inhibits the OATP2B1-mediated study involving felodipine.19,20 On the other hand, grapefruit absorption of aliskiren from gut lumen. To our knowledge, this juice also inhibits intestinal OATP1A2 and OATP2B16,7,21–23 is the first study demonstrating that grapefruit juice may be a and has been shown to reduce the bioavailability of orally clinically important inhibitor of OATP2B1.
1Department of Clinical pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. Correspondence: M Niemi Received 26 February 2010; accepted 25 April 2010; advance online publication 21 July 2010. CliniCal pharmaCology & TherapeuTiCs | VOLUME 88 NUMBER 3 | sEptEMBER 2010
Grapefruit juice also slightly shortened the t½ of aliskiren. Similar to its effects on the pharmacokinetics of aliskiren, In previous studies, repeated consumption of grapefruit juice grapefruit juice has been shown to markedly reduce the bio- was shown to slightly prolong the t½ of some CYP3A4 substrate availability of oral y administered fexofenadine (63% decrease in drugs.25,26 Aliskiren undergoes enterohepatic circulation, char- AUC) and celiprolol (87% decrease in AUC), probably by inhib- acterized by double peaks in its plasma concentration curves.4,17 iting intestinal OATP influx transporters.12,21 Fexofenadine has The shortened t½ may have resulted from inhibition of the intes- been identified as a substrate of both OATP1A2 and OATP2B1, tinal reabsorption of aliskiren during enterohepatic circulation. although one study failed to show OATP2B1-mediated trans- The finding that the Cmax of aliskiren occurred at a later time port of fexofenadine in transiently transfected HeLa cel s.21,23,24 point during the grapefruit-juice phase than during the water When directly compared, the OATP1A2-mediated influx of phase is consistent with delayed absorption of aliskiren in asso- fexofenadine was much greater than the OATP2B1-mediated ciation with inhibition of intestinal OATP2B1.
influx.23 Celiprolol is a substrate of OATP1A2,27 but there are no published studies on possible OATP2B1-mediated transport In one study, concomitant ingestion of 300 ml of grapefruit juice and fexofenadine decreased the AUC of fexofenadine by 52%.23 When 300 ml of grapefruit juice was ingested 2 h before fexofenadine, the AUC was decreased by 38%, but when the juice was ingested 4 h before fexofenadine, there was no effect.23 It is likely that the effect of grapefruit juice on inhibition of OATP2B1 is of similar duration. Thus, it is possible that ingestion of only a single 200–400 ml dose of grapefruit 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 inges- tion of 200 ml of grapefruit juice three times daily.
In contrast to its effects on aliskiren, grapefruit juice was shown to increase the AUC of the OATP2B1 substrates ator- Figure 1 Geometric mean (90% confidence interval) plasma concentrations
vastatin (2.5-fold) and amiodarone (1.5-fold).25,28–30 Both of aliskiren in 11 healthy volunteers. the volunteers ingested 200 ml of atorvastatin and amiodarone are significantly metabolized by grapefruit 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 grapefruit-juice or water dose of CYP3A4,13,30 and the inhibition of CYP3A4 by grapefruit juice is the day. Inset depicts the same data on a semilogarithmic scale.
probably the main explanation for these interactions. Moreover, table 1 Pharmacokinetic variables of and plasma renin activity response to a single 150-mg oral dose of aliskiren in 11 healthy
volunteers
Variable

Water phase (control)
grapefruit-juice phase
geometric mean ratio (90% Ci)
P value
the volunteers ingested 200 ml of grapefruit 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 grapefruit-juice or water dose of the day. Data are given as geometric means (90% CI), tmax as medians (range), and t½, ke, and plasma renin activity as mean values ± sD.
Ae, amount excreted into urine within 12 h; AUC0–72 h, area under the plasma concentration–time curve from 0 to 72 h; AUC0–∞, area under the plasma concentration–time curve from time 0 to ∞; baseline, before the administration of aliskiren; CI, confidence interval; CL/F, oral clearance; CLR, renal clearance; Cmax, peak plasma concentration; ke, elimination rate constant; t½, elimination half-life; tmax, time to Cmax.
aMean difference (90% CI).
VOLUME 88 NUMBER 3 | sEptEMBER 2010 | www.nature.com/cpt
Figure 2 Individual Cmax, AUC, and t½ values of aliskiren in 11 healthy volunteers. the volunteers ingested 200 ml of grapefruit 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 grapefruit-juice or water dose of the day. AUC, area under the plasma concentration–time curve; Cmax, peak plasma concentration; t½, elimination half-life.
grapefruit juice has no significant effect on the pharmacokinet- excluded because of noncompliance with the diet. Five women and ics of the OATP2B1 substrates glyburide (glibenclamide) and six men completed the study. Their mean ± SD age was 22 ± 2 years pravastatin, suggesting that OATP2B1 is not important for the (range, 20–28 years), mean height 178 ± 8 cm (range, 163–190 cm), and mean weight 71 ± 10 kg (range, 55–92 kg). Each participant’s health intestinal absorption of these compounds.22,24,25,31 was ascertained by medical history, clinical examination, and labora- Several constituents of grapefruit juice—e.g., naringin, narin- tory tests. Subjects with a systolic blood pressure <100 mm Hg were genin, quercetin, bergamottin, and 6′,7′-dihydroxybergamottin— not included in the study. None of the subjects was on any continuous have been shown to inhibit OATP2B1 in vitro.22 Naringin is medication, and none was a tobacco smoker.
considered the major constituent responsible for inhibition of study design. The study protocol was approved by the Coordinating Ethics
OATP1A2 in vivo,32 suggesting that it could also play an impor- Committee of the Helsinki and Uusimaa Hospital District and by the tant role in the inhibition of OATP2B1 by grapefruit juice in vivo. National Agency for Medicines. In a randomized crossover study with two In addition to the direct inhibition of OATP2B1 by grapefruit- phases and a washout period of 2 weeks, the participants ingested either juice constituents, other mechanisms may also contribute to the 200 ml of normal-strength grapefruit juice (Valio Greippitäysmehu; Valio, Helsinki, Finland) or water three times a day at 8 am, 12 noon, and 8 pm for interaction between grapefruit juice and aliskiren. Theoretical y, 5 days to ensure nearly maximal CYP3A4 inhibition and to investigate the carbohydrates or organic acids present in grapefruit juice could possible effect of grapefruit juice on aliskiren elimination. On day 3, after form a poorly absorbed complex with aliskiren. Also, grape- an overnight fast, they ingested a single 150-mg dose of aliskiren (Rasilez; fruit juice might alter intestinal fluid volume through an osmotic Novartis, Horsham, UK) with 200 ml of grapefruit juice or water at 8 am. effect, the carbohydrates of grapefruit juice might delay stomach A standardized warm meal was served 4 h after aliskiren and standardized light meals after 7 and 10 h. As a safety assessment, systolic and diastolic emptying, or the acidic pH of grapefruit juice might affect the blood pressures were measured prior to and at 2, 4, 7, 9, 12, and 24 h after solubility and ionization of aliskiren.
aliskiren ingestion. The measurements were made from the forearm, using In previous studies, the P-glycoprotein and CYP3A4 inhibi- an automatic oscil ometric blood pressure monitor (Omron M5-I; Omron tors itraconazole and cyclosporine have been shown to raise the Healthcare Europe BV, Hoofddorp, The Netherlands), with the participant AUC of aliskiren approximately sevenfold and approximately in the seated position. The participants were under direct medical supervi- sion for 12 h after the administration of aliskiren. No significant changes fivefold, respectively.10–15,17,18 Considering, as well, the marked in blood pressure were observed, nor were adverse effects reported. Use effect of the OATP2B1 inhibitor grapefruit juice on aliskiren of grapefruit products was prohibited during the study, starting from 2 pharmacokinetics, it appears that aliskiren is very susceptible to weeks before the first day of administration of aliskiren. Use of all drugs inhibition of both influx and efflux transporters, and possibly of was prohibited for 1 week, and use of apple juice, orange juice, and alcohol for 2 days before aliskiren administration and for 72 h thereafter.
Timed ethylenediaminetetraacetic acid blood samples (5–15 ml each) In this study, grapefruit juice had no significant effect on the were drawn before aliskiren ingestion and at various time points up to renin activity response to a single dose of aliskiren in healthy vol- 72 h after ingestion. Plasma was separated within 30 min. Urine was col- unteers. However, the pharmacodynamic response to aliskiren in lected for up to 12 h after aliskiren ingestion. The samples were stored at patients with hypertension may be different from that in normo- tensive individuals. The pharmacokinetics of aliskiren, however, is Determination of aliskiren concentrations and renin activity. The con-
similar in hypertensive and normotensive individuals.2 Therefore, centrations of aliskiren in plasma and urine were quantified using an clinicians should be aware that continuous use of grapefruit juice Applied Biosystems SCIEX QTrap LC/MS/MS system (Sciex Division of may decrease the antihypertensive efficacy of aliskiren.
MDS, Toronto, Ontario, Canada).17,33 Acebutolol served as an internal In conclusion, grapefruit juice greatly reduces the plasma con- standard. The lower limit of quantification was 0.25 ng/ml for aliskiren in plasma and 9 ng/ml for aliskiren in urine. The between-day coefficient centrations of aliskiren, probably by inhibiting its OATP2B1- of variation was ≤10% at relevant concentrations in plasma (n = 6), and mediated influx in the small intestine. The concomitant use of the intraday coefficient of variation was ≤4.8% at relevant concentra- aliskiren and grapefruit juice is best avoided.
tions in urine (n = 6). Plasma renin activity was measured using a radio- immunoassay method (RENCTK; DiaSorin, Saluggia, Italy) at Medix MethoDs
subjects.
Twelve healthy volunteers participated in the study after
Pharmacokinetics and pharmacodynamics. Aliskiren pharmacokinetics
giving written informed consent, but one subject was subsequently were characterized by estimating Cmax, time to Cmax (tmax), elimination CliniCal pharmaCology & TherapeuTiCs | VOLUME 88 NUMBER 3 | sEptEMBER 2010
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