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The change of pharmacokinetics of fexofenadine enantiomers through the single and simultaneous grapefruit juice ingestion
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Drug Metabolism and Pharmacokinetics xxx (2015) 1e6
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Regular article
The change of pharmacokinetics of fexofenadine enantiomers through the single and simultaneous grapefruit juice ingestion Q3
Yumiko Akamine a, Masatomo Miura a, *, Hisakazu Komori b, Ikumi Tamai b, Ichiro Ieiri c, Norio Yasui-Furukori d, Tsukasa Uno e a
Department of Pharmacy, Akita University Hospital, Akita, Japan Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan d Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki, Japan e Department of Pharmacy, Zikeikai-Aoimori Hospital, Aomori, Japan b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 3 April 2015 Received in revised form 3 June 2015 Accepted 19 June 2015 Available online xxx
The stereoselective pharmacokinetics of fexofenadine are associated with OATP2B1-mediated transport, and grapefruit juice (GFJ) is an inhibitor of OATP2B1. Therefore, in this study, we aimed to investigate whether and to what extent GFJ ingestion affected the pharmacokinetics of fexofenadine enantiomers in healthy subjects. In a randomized, two-phase, open-label, crossover study, 14 subjects received 60 mg of racemic fexofenadine simultaneously with water or GFJ. Ingestion of GFJ significantly decreased the areas under the plasma concentration-time curve (AUC0e24) for (R)- and (S)-fexofenadine by 39% and 52%, respectively. Subsequently, GFJ increased the mean R/S ratio of the AUC0e24 from 1.58 to 1.96 (P < 0.05). Although GFJ greatly reduced the amounts of (R)- and (S)-fexofenadine excreted into the urine (Ae0e24) by 52% and 61%, respectively, the mean R/S ratios of Ae0e24 and the renal clearances of both enantiomers were unchanged between the control and GFJ phases. GFJ, an OATP2B1 inhibitor, significantly reduced the plasma concentrations of fexofenadine enantiomers, exhibiting clinically moderate effects. The present results suggested that changes in OATP2B1 activity by GFJ may alter the stereoselective pharmacokinetics of fexofenadine and that reduced intestinal OATP2B1 activity may affect the stereoselectivity of fexofenadine.
Keywords: Enantiomer Fexofenadine Grapefruit juice OATP2B1 Pharmacokinetics
Q1
Copyright © 2015, Published by Elsevier Ltd on behalf of The Japanese Society for the Study of Xenobiotics.
1. Introduction Drugedrug interactions can occur through various drug transporters, and such interactions may cause substantial changes in the pharmacokinetics of orally administered drugs [1e3]. Similarly, studies have suggested that the mechanisms of foodedrug interactions may be related to the activities of several drug transporters [4,5]. In particular, grapefruit juice (GFJ) has been shown to have multiple interactions with many drugs, leading to increased side effects or loss of therapeutic effects [6,7]. Since GFJ has multiple inhibitory effects on drug transport and metabolic systems, complex GFJ-drug interactions have been observed [6e8]. For example, GFJ significantly increases the bioavailability of calcium
* Corresponding author. Akita University Hospital, Akita 010-8543, Japan. Tel.: þ81 18 884 6310; fax: þ81 18 836 2628. E-mail address: [email protected] (M. Miura).
channel blockers, immunosuppressants, and anticancer agents (molecular targeted drugs) [6]. The primary drug-interaction mechanisms are likely caused by the inhibition of intestinal cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp) [6,9,10]. Since CYP3A substrates overlap considerably with P-gp substrates [11], the inhibitory effects of GFJ may occur through the combination of CYP3A and P-gp. Additionally, GFJ causes decreased exposure to several drugs because GFJ inhibits organic anion-transporting polypeptides (OATPs), i.e., OATP1A2 and e2B1 [12e15]. GFJ decreases the oral bioavailability of OATP1A2 and/or OATP2B1 substrate drugs, such as fexofenadine, aliskiren, celiprolol, talinolol, and ciprofloxacine. OATP1A2 and OATP2B1 are expressed on the luminal membrane of small intestinal enterocytes and potentially participate in the active absorption of drugs [12,16e19]. Interestingly, the expression level of OATP2B1 is relatively higher than that of OATP1A2 [20,21]. Previous reports have shown that OATP2B1 mRNA levels are expressed in all intestinal sections (e.g., 0.06 for the ileum and
http://dx.doi.org/10.1016/j.dmpk.2015.06.005 1347-4367/Copyright © 2015, Published by Elsevier Ltd on behalf of The Japanese Society for the Study of Xenobiotics.
Please cite this article in press as: Akamine Y, et al., The change of pharmacokinetics of fexofenadine enantiomers through the single and simultaneous grapefruit juice ingestion, Drug Metabolism and Pharmacokinetics (2015), http://dx.doi.org/10.1016/j.dmpk.2015.06.005
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0.02 for the duodenum and colon ascendens; the numbers represent copy numbers relative to that in the villin, with significantly increased expression when the number is larger than 0.01). In contrast, OATP1A2 mRNA is not detectable or expressed at negligible levels in all intestinal sections (e.g., 0.003 for the ileum, 0.0002 for the duodenum, and 0.0004 for the colon ascendens) [22]. Similarly, other reports have shown that OATP2B1 protein is expressed in the small intestine in humans, while OATP1A2 protein could not be detected [20]. Taken together, these data show that OATP2B1 is the predominantly expressed isoform in the intestine and may be responsible for the observed OATP function in the small intestine. Therefore, although the contribution of OATP1A2 to GFJ-drug interactions cannot be ruled out, OATP2B1 may be the key determinant of intestinal OATP-mediated transport. Characterization of fexofenadine enantiomers after racemic dosing indicates the occurrence of stereoselectivity; the plasma concentration of (R)-fexofenadine is approximately 1.5-fold higher than that of the (S)-enantiomer [23,24]. These pharmacokinetics primarily depend on the activities of multiple transporters, including P-gp and OATPs [25]. Previous human studies have revealed that P-gp inhibitors, such as itraconazole and verapamil, significantly increase the concentrations of both enantiomers through inhibition of the efflux activity of intestinal Pgp [26,27]. In contrast, our recent report indicated that polymorphisms in the SLCO gene, which encodes OATP, are more highly associated with the pharmacokinetics of fexofenadine enantiomers than polymorphisms in the ABCB1 gene (also known as MDR1), which encodes P-gp [28]. In addition, rifampicin is a potent P-gp inducer and OATP inhibitor and has been shown to cause a marked increase in the concentrations of both enantiomers of fexofenadine [29,30]. These results suggested that rifampicin may inhibit the OATP-mediated transport of both enantiomers in the liver, and this effect may be greater than the induction effect on P-gp. In addition, these results imply that the drug and food interactions of fexofenadine occurring through OATP-mediated transport are likely to exhibit different effects in the intestine and liver. To date, the differences in the pharmacological effects and safety profiles of fexofenadine enantiomers have not been fully established. Although Robbins et al. reported that the two enantiomers are pharmacologically identical [23], our recent in vitro binding assays demonstrated that (S)-fexofenadine is a more potent human histamine H1 receptor antagonist than (R)-fexofenadine [30]. Therefore, (S)-fexofenadine shows larger receptor occupancy and consequently makes a greater contribution to the pharmacological response than (R)-fexofenadine. Moreover, our most recent study indicated that apple juice (AJ) significantly decreases the oral bioavailability of both fexofenadine enantiomers [31]. In an in vitro uptake study, the uptake of both fexofenadine enantiomers into oocytes injected with OATP2B1 cRNA is significantly higher than that into oocytes injected with water, and this effect is greater for (R)-fexofenadine [31]. In addition, AJ significantly decreases the uptake of both enantiomers into oocytes injected with OATP2B1 cRNA [31]. Furthermore, we have shown that the uptake of both enantiomers is the same in P-gp-, OATP1B3-, OAT3-, and multidrug and toxic compound extrusion 1 (MATE1)-expressing cells [30]. Thus, these results suggest that OATP2B1 may be the main factor mediating the stereoselectivity of fexofenadine and fexofenadine enantiomer pharmacokinetics. To date, no reports have examined the effects of GFJ on the stereoselectivity of co-administered drugs. Therefore, this study was designed to examine whether and to what extent GFJ, administered once orally, affected the pharmacokinetics of fexofenadine enantiomers.
2. Methods 2.1. Subjects Most of the 14 healthy Japanese volunteers (11 men and 3 women) who were included in this study had participated in our previous study [28]. Each subject was deemed physically healthy by a clinical examination and routine laboratory testing and had no history of significant medical illnesses or hypersensitivity to any drugs. The volunteers had a mean (±SD) age of 25.0 (±4.9) years and a mean body weight of 57.6 (±7.5) kg. This study was approved by the Ethics Committee of the Hirosaki University School of Medicine, and all subjects gave written informed consent before participating. 2.2. Study design A randomized crossover study design in two phases was conducted in intervals of at least 2 weeks. Following an overnight fast, healthy subjects simultaneously received 60 mg of racemic fexofenadine hydrochloride (Allegra; Sanofi K.K., Tokyo, Japan) with 250 mL of water or GFJ at 9:00 AM. The extract from tablets (Allegra) did not have optical activity; as a result, fexofenadine was administered as a racemic mixture, i.e. a 50/50 mixture of enantiomers, where the dose was 30 mg for each fexofenadine enantiomer. The GFJ (Tropicana; Kirin Beverage Co. Ltd., Tokyo, Japan) used in this study was of normal strength. Volunteers did not ingest any medication, fruit juices, or grapefruit, orange, or grapefruit products for at least 7 days before either of the study phases. No meals or beverages were allowed until 4 h after fexofenadine administration. In addition, the use of alcohol, tea, and coffee was forbidden during the test period. 2.3. Plasma and urine collection and determination of fexofenadine enantiomer concentrations Blood samples (10 mL each) were drawn into heparinized tubes before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 h after administration of fexofenadine, and the plasma was immediately separated. Immediately prior to fexofenadine administration, urine was collected to provide a blank sample. After fexofenadine administration, urine samples were collected during the subsequent 24-h period. Plasma and urine samples were stored at 20 C until assayed. Fexofenadine concentrations in plasma and urine were determined using a high-performance liquid chromatography (HPLC) method that had been developed in our laboratory [32]. In brief, following the addition of diphenhydramine (50 ng) in methanol (10 mL) as an internal standard to 400 mL of plasma, the plasma sample was diluted with 600 mL water and was vortexed for 30 s. For urine samples, diphenhydramine (50 ng) in methanol (10 mL) was added to 100 mL urine, and the sample was then diluted with 900 mL water. These sample mixtures were applied to an Oasis HLB extraction cartridge that had been previously activated with methanol and water (1.0 mL each). The cartridge was successively washed with 1.0 mL of water and 1.0 mL of 40% methanol in water followed by elution with 1.0 mL of 100% methanol. Eluates were evaporated to dryness under vacuum at 40 C using a rotary evaporator (Iwaki, Tokyo, Japan). The residue was dissolved in 50 mL methanol and was vortexed for 30 s. Approximately 50 mL of the mobile phase was added, and the sample was vortexed for another 30 s. A 50-mL aliquot of the sample was then processed using the HPLC apparatus. The HPLC column was a Chiral CD-Ph (250 mm 4.6 mm i.d.; Shiseido, Tokyo, Japan), and the mobile phase was 0.5% KH2PO4 (pH 3.5)-acetonitrile (65:35, v:v). The flow rate was 0.5 mL/min at ambient temperature, and sample
Please cite this article in press as: Akamine Y, et al., The change of pharmacokinetics of fexofenadine enantiomers through the single and simultaneous grapefruit juice ingestion, Drug Metabolism and Pharmacokinetics (2015), http://dx.doi.org/10.1016/j.dmpk.2015.06.005
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detection was performed at 220 nm. The lower limit of quantification was 25 ng/mL for both (R)- and (S)-fexofenadine, and the limit of detection was 12.5 ng/mL for each enantiomer of fexofenadine. The validated concentration range of this assay for plasma and urine samples was 25e625 ng/mL for both enantiomers. The within- and between-day coefficients of variation were less than 13.6%, and accuracy was within 8.8% over the linear range of both analytes. The plasma and urine samples after GFJ treatment did not have any interfering peaks in the fexofenadine assay. The plasma and urine blank samples that were collected before fexofenadine administration presented no detectable fexofenadine peak in the assay.
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figures. Differences in the pharmacokinetic parameters between (R)- and (S)-fexofenadine and between the control phase and the treatment phase as well as in the R/S ratio of the AUC0e24, Ae0e24, and CLrenal between the control phase and the treatment phase were analyzed using paired t-tests. Statistical analysis was performed using SPSS version 20.0 for Windows (SPSS, IBM Japan Inc., Tokyo, Japan) and WinNonlin (Version 5.2; Pharsight Co., Mountain View, CA, USA). Differences with P-values of less than 0.05 were considered statistically significant. 3. Results 3.1. Plasma pharmacokinetics of fexofenadine enantiomers
2.4. Pharmacokinetic data analysis Pharmacokinetic analysis of fexofenadine enantiomers was performed with a standard, noncompartmental method using WinNonlin (Pharsight Co., Mountain View, CA, Version 4.0.1). The maximum plasma concentration (Cmax) and time to reach Cmax (tmax) were determined directly from the observed data. The elimination rate constant (ke) for fexofenadine was obtained by linear regression analysis using at least 3 sampling points from the terminal log-linear declining phase to the last measurable concentration. The elimination half-life (t1/2) was calculated as 0.693 divided by ke. The AUC from time zero to the last sampling time (AUC0e24) was calculated by the trapezoidal rule. The apparent oral clearance (CL/F) was obtained from the equation CL/F ¼ Dose/ AUC0e24, where the Dose was 30 mg for each fexofenadine enantiomer. Renal clearance (CLrenal) was obtained from the following equation: CLrenal ¼ Ae0e24/AUC0e24, where Ae is the amount of fexofenadine excreted into the urine within a 24-h period. 2.5. Statistical analysis The results are expressed as the mean and 95% confidence interval (CI) in the table or the mean þ standard deviation (SD) in the
None of the enrolled subjects reported any adverse events during the study, and the subjects completed all phases according to the study protocol. The mean (þSD) plasma concentration-time profiles of the fexofenadine enantiomers after a single oral dose of 60 mg of fexofenadine hydrochloride are shown in Fig. 1 for both the control (water) and GFJ-treated phases. The pharmacokinetic parameters are summarized in Table 1. Single ingestion of GFJ greatly reduced the plasma concentrations of both fexofenadine enantiomers compared with those from the water phase (Figs. 2 and 3). GFJ also altered all of the pharmacokinetic parameters except t1/2 and tmax (Table 1). On the other hand, in the water phase, the plasma concentration of (R)-fexofenadine at all time points was higher than that of the corresponding (S)-enantiomer, and the mean AUC0e24 R/S ratio was 1.58 (95% CI, 1.36e1.81; Fig. 1 and Table 1). GFJ significantly decreased the AUC0e24 values of both enantiomers in all subjects except one (P < 0.001 for both enantiomers; Fig. 2). Additionally, these effects were dependent on the baseline value of each enantiomer, and a highly significant correlation was observed (R2 ¼ 0.7169, P < 0.001 for (R)-fexofenadine; R2 ¼ 0.9300, P < 0.001 for (S)-fexofenadine; Fig. 3). GFJ increased the mean R/S ratio of the AUC0e24 from 1.58 to 1.96 (95% CI, 1.65e2.27; P < 0.05; Table 1).
B (S)-foxofenadine concentration (ng/mL)
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Fig. 1. A: Mean (þSD) plasma concentration-time curves of (R)-fexofenadine following a single oral administration of 60 mg fexofenadine hydrochloride in 14 healthy volunteers treated with water (open squares) or GFJ (closed squares). B: Mean (þSD) plasma concentration-time curves of (S)-fexofenadine following a single oral administration of 60 mg fexofenadine hydrochloride in 14 healthy volunteers treated with water (open circles) or GFJ (closed circles).
Please cite this article in press as: Akamine Y, et al., The change of pharmacokinetics of fexofenadine enantiomers through the single and simultaneous grapefruit juice ingestion, Drug Metabolism and Pharmacokinetics (2015), http://dx.doi.org/10.1016/j.dmpk.2015.06.005
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Table 1 Effect of GFJ on pharmacokinetic parameters of fexofenadine enantiomers.
(R)-fexofenadine
(S)-fexofenadine
Parameters
control
＋GFJ
Ratio to control
t1/2 (h) tmax (h) (range) Cmax (ng/mL) AUC0e24 (ng･h/mL) CL/F (L/h) Ae0e24 (mg) CLrenal (L/h) t1/2 (h) tmax (h) (range) Cmax (ng/mL) AUC0e24 (ng･h/mL) CL/F (L/h) Ae0e24 (mg) CLrenal (L/h)
4.0 (3.4e4.6) 1.4 (0.5e3.0) 131 (111e151) 777 (660e893) 41 (36e47) 3.2 (2.4e4.1) 4.5 (3.2e5.7) 3.3 (2.9e3.8)y 1.5 (0.5e4.0) 110 (93e126)yyy 562 (427e697)yyy 62 (50e74)yyy 4.0 (3.1e4.8) 8.4 (6.4e10.4)yyy 1.58 (1.36e1.81) 0.61 (0.42e0.80)
4.3 (3.7e4.9) 2.0 (1.0e4.0) 68 (54e81)*** 461 (353e569)*** 75 (61e88)*** 1.4 (0.9e1.8)** 3.4 (2.1e4.7) 3.5 (3.1e4.0)yy 2.1 (1.0e4.0) 45 (34e55)***yyy 244 (178e309)***yyy 143 (117e169)***yyy 1.4 (1.0e2.0)*** 6.5 (4.4e8.7)yyy 1.96 (1.65e2.27)* 0.50 (0.45e0.55)
1.20 1.84 0.55 0.61 1.86 0.48 0.88 1.21 1.92 0.44 0.48 2.56 0.39 0.78 1.39 1.06
R/S ratio of AUC R/S ratio of CLrenal
(0.90e1.50) (1.03e2.64) (0.44e0.67) (0.48e0.74) (1.52e2.20) (0.33e0.63) (0.55e1.22) (0.95e1.48) (1.07e2.77) (0.33e0.54) (0.35e0.61) (1.92e3.22) (0.27e0.52) (0.40e1.16) (1.09e1.69) (0.74e1.39)
*P < 0.05, **P < 0.01, ***P < 0.001, between control phase and GFJ phase. yP < 0.05, yyP < 0.01, yyyP < 0.001, between (R)-fexofenadine and (S)-fexofenadine. Data are shown as mean and 95% confidence interval; tmax data are shown as a median with a range.
3.2. Urinary excretion of fexofenadine enantiomers In the control phase, the Ae0e24 of (S)-fexofenadine was slightly higher than that of (R)-fexofenadine; however, the difference did not reach statistical significance (P ¼ 0.266; Fig. 4). The mean CLrenal of (S)-fexofenadine was significantly higher than that of (R)-fexofenadine (P < 0.001; Table 1). GFJ greatly decreased the mean Ae0e24 values of both enantiomers (P < 0.01 for the (R)-enantiomer, P < 0.001 for the (S)-enantiomer; Fig. 4 and Table 1). In addition, compared to the control, GFJ did not change the mean CLrenal of either enantiomer. GFJ slightly decreased the mean R/S ratio of the CLrenal from 0.61 (95% CI, 0.42e0.80) to 0.50 (95% CI, 0.45e0.55), but this difference was not statistically significant (P ¼ 0.293; Table 1). 4. Discussion In this study, we investigated the effects of a single ingestion of GFJ on the pharmacokinetics of fexofenadine enantiomers. The results showed that GFJ significantly decreased the mean Cmax and
AUC0e24 of both enantiomers, even after only a single ingestion (Figs. 1 and 2). No significant differences were shown in pharmacokinetic parameters involving tmax, t1/2, and CLrenal between the control and GFJ phases (Table 1). If this effect of GFJ could be attributed to inhibition of hepatic OATP-mediated transport, the plasma concentrations of both enantiomers would have been somewhat enhanced, as described previously [1e3]. In addition, recent studies have found that OATP2B1 is a major OATPtransporter in the small intestine and that the uptake/transport of fexofenadine in oocytes injected with OATP2B1 cRNA is significantly decreased in the presence of GFJ [15,33,34]. Therefore, these results suggested that GFJ inhibited the intestinal OATP2B1mediated transport of fexofenadine enantiomers and may alter the pharmacokinetics of both enantiomers. Additionally, a previous clinical study found that a single ingestion of AJ significantly decreases the AUC0e24 for (R)- and (S)fexofenadine by 49% and 59%, respectively [31], while the present single-intake GFJ study showed that the AUC0e24 values of (R)- and (S)-fexofenadine decreased by 39% and 52%, respectively (Table 1). A recent in vitro study reported that co-incubation with AJ reduces
Fig. 2. A: Individual changes in the AUC0e24 of (R)-fexofenadine following a single oral administration of 60 mg fexofenadine hydrochloride in 14 healthy volunteers treated with water or GFJ. B: Individual changes in the AUC0e24 of (S)-fexofenadine following a single oral administration of 60 mg fexofenadine hydrochloride in 14 healthy volunteers treated with water or GFJ. ***P < 0.001, between control phase and GFJ phase.
Please cite this article in press as: Akamine Y, et al., The change of pharmacokinetics of fexofenadine enantiomers through the single and simultaneous grapefruit juice ingestion, Drug Metabolism and Pharmacokinetics (2015), http://dx.doi.org/10.1016/j.dmpk.2015.06.005
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differences between in vivo and in vitro results. However, the present study suggested that a single ingestion of GFJ could possibly be of moderate clinical significance for patients receiving OATP2B1 substrate drugs, such as fexofenadine. These findings imply that the inhibitory effects of GFJ were similar to or less than those of AJ. In our recent in vitro study [31], uptake into oocytes injected with OATP2B1 cRNA was higher for (R)-fexofenadine than (S)-fexofenadine. Consistent with these results, the present in vivo analysis demonstrated that the plasma concentration of (R)fexofenadine was higher than the corresponding (S)-enantiomer during the control phase (Fig. 1). In addition, in our former in vitro study, the stereoselectivity of fexofenadine enantiomer transport was not found in P-gp-, OATP1B3-, OAT3-, or MATE1-expressing cells [30]. Furthermore, OATP2B1 plays an important role in the hepatic disposition of substrate drugs [38]. Thus, if hepatic OATP2B1-mediated transport was a primary determinant of the stereoselective pharmacokinetics of fexofenadine, (R)-fexofenadine may be excreted primarily into the bile, and the plasma concentration of (S)-fexofenadine would be higher than the corresponding (R)-enantiomer. On the other hand, similar to previous studies, the Ae0e24 of (S)-fexofenadine was almost the same as that of (R)-fexofenadine during both the control and GFJ phases (Fig. 4). This result suggested that the urinary excretion of fexofenadine enantiomers was unlikely to be stereoselectivity because P-gp, OAT3, and MATE plays some roles in fexofenadine urinary excretion and those transporters disappear to demonstrate the stereoselectivity of fexofenadine enantiomers. These results strongly support that intestinal OATP2B1-mediated transport may be a crucial determinant of the stereoselective pharmacokinetics of fexofenadine enantiomers. In additive to the effect of OATP2B1, an in vivo and in vitro studies have been reported that OATP1A2 is contributed to the uptake of fexofenadine in the small intestine and that verapamil inhibited the uptake of fexofenadine through OATP1A2-mediated transport [39]. Unfortunately, in the present study, although the authors were not able to determine the effect to which OATP1A2 contributed to the stereoselectivity of fexofenadine in in vitro study using oocytes, our previous in vivo report showed that verapamil altered the stereoselectivity of fexofenadine [27]. Therefore, these findings may imply the potential that OATP1A2 takes part in the stereoselective pharmacokinetics of fexofenadine and GFJ inhibits both OATP1A2-and OATP2B1-mediated transports of fexofenadine enantiomers. However, to clarify these contributions to fexofenadine enantiomer pharmacokinetics, further in vivo and in vitro studies will be needed.
Fig. 3. Changes in the AUC0e24 values of (R)- and (S)-fexofenadine following ingestion of GFJ plotted against the AUC0e24 during the water phase for each individual (n ¼ 14). (R)-fexofenadine (open squares) and (S)-fexofenadine (closed circles).
the inhibitory effects of OATP2B1 [15]; the apparent half-maximal inhibitor concentrations (IC50) were in the order of GFJ < orange juice (OJ) < AJ, and the inhibitory effect of GFJ was most potent. However, the present results indicated that the GFJ-dependent reductions in plasma concentrations of fexofenadine enantiomers were similar to or less than those induced by AJ and that the inhibitory effects of AJ were greater than those of GFJ. These results are consistent with another in vivo report [12]. Furthermore, Shirasaka et al. reported that naringin, a component in GFJ, is the predominant molecule responsible for the inhibition of OATP2B1, while phloridzin and phloretin are the primary components contributing to inhibition of OATP2B1-mediated uptake in AJ [15]. Naringin has also been reported to inhibit P-gp [35,36], and P-gp significantly contributes to the pharmacokinetics of fexofenadine enantiomers [24,25,37]. Based on these previous studies, naringin in GFJ would be expected to inhibit both P-gp- and OATP2B1-mediated transport in relation to fexofenadine pharmacokinetics, and the reduced plasma concentrations of fexofenadine enantiomers in response to OATP2B1 inhibition may be attenuated by naringin-induced inhibition of P-gp, resulting in the observed
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Fig. 4. A: Mean (þSD) cumulative amount of (R)-fexofenadine excreted into the urine during water (open squares) or GFJ (closed squares) administration. B: Mean (þSD) cumulative amount of (S)-fexofenadine excreted into the urine during water (open circles) or GFJ (closed circles) ingestion.
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Additionally, a previous clinical study showed that single ingestion of AJ increased the mean R/S ratio of the AUC0e24 from 1.49 to 2.00 [31]. Similarly, the present single-intake GFJ study showed that the mean R/S ratio of the AUC0e24 increased significantly from 1.58 to 1.96 (Table 1). Furthermore, similar to the results of the AJ study [31], the inhibitory effects of GFJ on fexofenadine enantiomers were highly correlated with the baseline AUC0e24 value of each enantiomer; the more dramatic change in ratio following ingestion of GFJ may be due to the higher AUC0e24 value in the control (Fig. 3). Therefore, these results indicated that the inhibitory effects of AJ and GFJ on OATP2B1-mediated transport were similar, despite the differences in primary inhibitory components between the two juice types. Moreover, both juices are likely to have greater inhibitory effects on (S)-fexofenadine. Accordingly, these results imply that the concentration ranges of the main components in GFJ and AJ may be more sufficient for the inhibition of (S)-fexofenadine than for that of (R)-fexofenadine. However, further in vivo and in vitro studies will be required to elucidate the specific mechanism. In conclusion, the present study indicated that a single ingestion of GFJ could be of moderate clinical significance for patients receiving OATP2B1 substrate drugs, such as fexofenadine. Furthermore, our results suggested that changes in OATP2B1 activity in response to GFJ may alter the stereoselective pharmacokinetics of fexofenadine and that reduced intestinal OATP2B1 activity may affect the stereoselectivity of fexofenadine. Conflict of interest statement The authors have no conflicts of interest in relation to this paper. Acknowledgments We are very grateful to Prof. Hiroyuki Kusuhara (Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo) for providing grateful comments on this study. References [1] Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, Chu X, et al. Membrane transporters in drug development. Nat Rev Drug Discov 2010;9: 215e36. [2] Kalliokoski A, Niemi M. Impact of OATP transporters on pharmacokinetics. Br J Pharmacol 2009;158:693e705. [3] Shitara Y. Clinical importance of OATP1B1 and OATP1B3 in drug-drug interactions. Drug Metab Pharmacokinet 2011;26:220e7. [4] Bailey DG. Fruit juice inhibition of uptake transport: a new type of food-drug interaction. Br J Clin Pharmacol 2010;70:645e55. [5] Dolton MJ, Roufogalis BD, McLachlan AJ. Fruit juices as perpetrators of drug interactions: the role of organic anion-transporting polypeptides. Clin Pharmacol Ther 2012;92:622e30. [6] Seden K, Dickinson L, Khoo S, Back D. Grapefruit-drug interactions. Drugs 2010;70:2373e407. [7] Uno T, Yasui-Furukori N. Effect of grapefruit juice in relation to human pharmacokinetic study. Curr Clin Pharmacol 2006;1:157e61. [8] Rodriguez-Fragoso L, Martinez-Arismendi JL, Orozco-Bustos D, ReyesEsparza J, Torres E, Burchiel SW. Potential risks resulting from fruit/vegetabledrug interactions: effects on drug-metabolizing enzymes and drug transporters. J Food Sci 2011;76:R112e24. [9] Hanley MJ, Cancalon P, Widmer WW, Greenblatt DJ. The effect of grapefruit juice on drug disposition. Expert Opin Drug Metab Toxicol 2011;7: 267e86. [10] Bailey DG, Dresser GK. Interactions between grapefruit juice and cardiovascular drugs. Am J Cardiovasc Drugs 2004;4:281e97. [11] Zhou SF. Drugs behave as substrates, inhibitors and inducers of human cytochrome P450 3A4. Curr Drug Metab 2008;9:310e22. [12] Dresser GK, Bailey DG, Leake BF, Schwarz UI, Dawson PA, Freeman DJ, et al. Fruit juices inhibit organic anion transporting polypeptide-mediated drug uptake to decrease the oral availability of fexofenadine. Clin Pharmacol Ther 2002;71:11e20.
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[23] Robbins DK, Castles MA, Pack DJ, Bhargava VO, Weir SJ. Dose proportionality and comparison of single and multiple dose pharmacokinetics of fexofenadine (MDL 16455) and its enantiomers in healthy male volunteers. Biopharm Drug Dispos 1998;19:455e63. [24] Miura M, Uno T, Tateishi T, Suzuki T. Pharmacokinetics of fexofenadine enantiomers in healthy subjects. Chirality 2007;19:223e7. [25] Cvetkovic M, Leake B, Fromm MF, Wilkinson GR, Kim RB. OATP and Pglycoprotein transporters mediate the cellular uptake and excretion of fexofenadine. Drug Metab Dispos 1999;27:866e71. [26] Tateishi T, Miura M, Suzuki T, Uno T. The different effects of itraconazole on the pharmacokinetics of fexofenadine enantiomers. Br J Clin Pharmacol 2008;65:693e700. [27] Sakugawa T, Miura M, Hokama N, Suzuki T, Tateishi T, Uno T. Enantioselective disposition of fexofenadine with the P-glycoprotein inhibitor verapamil. Br J Clin Pharmacol 2009;67:535e40. [28] Akamine Y, Miura M, Sunagawa S, Kagaya H, Yasui-Furukori N, Uno T. Influence of drug-transporter polymorphisms on the pharmacokinetics of fexofenadine enantiomers. Xenobiotica 2010;40:782e9. [29] Akamine Y, Miura M, Yasui-Furukori N, Ieiri I, Uno T. Effects of multiple-dose rifampicin 450 mg on the pharmacokinetics of fexofenadine enantiomers in Japanese volunteers. J Clin Pharm Ther 2015;40:98e103. [30] Kusuhara H, Miura M, Yasui-Furukori N, Yoshida K, Akamine Y, Yokochi M, et al. Effect of coadministration of single and multiple doses of rifampicin on the pharmacokinetics of fexofenadine enantiomers in healthy subjects. Drug Metab Dispos 2013;41:206e13. [31] Akamine Y, Miura M, Komori H, Saito S, Kusuhara H, Tamai I, et al. Effects of one-time apple juice ingestion on the pharmacokinetics of fexofenadine enantiomers. Eur J Clin Pharmacol 2014;70:1087e95. [32] Miura M, Uno T, Tateishi T, Suzuki T. Determination of fexofenadine enantiomers in human plasma with high-performance liquid chromatography. J Pharm Biomed Anal 2007;43:741e5. [33] Shirasaka Y, Mori T, Murata Y, Nakanishi T, Tamai I. Substrate- and dosedependent drug interactions with grapefruit juice caused by multiple binding sites on OATP2B1. Pharm Res 2014;31:2035e43. [34] Shirasaka Y, Shichiri M, Murata Y, Mori T, Nakanishi T, Tamai I. Long-lasting inhibitory effect of grapefruit and orange juices, but not grapefruit juice, on OATP2B1-mediated drug absorption. Drug Metab Dispos 2013;41:615e21. [35] Shirasaka Y, Suzuki K, Nakanishi T, Tamai I. Differential effect of grapefruit juice on intestinal absorption of statins due to inhibition of organic anion transporting polypeptide and/or P-glycoprotein. J Pharm Sci 2011;100:3843e53. [36] Shirasaka Y, Suzuki K, Shichiri M, Nakanishi T, Tamai I. Intestinal absorption of HMG-CoA reductase inhibitor pitavastatin mediated by organic anion transporting polypeptide and P-glycoprotein/multidrug resistance 1. Drug Metab Pharmacokinet 2011;26:171e9. [37] Akamine Y, Miura M, Yasui-Furukori N, Kojima M, Uno T. Carbamazepine differentially affects the pharmacokinetics of fexofenadine enantiomers. Br J Clin Pharmacol 2012;73:478e81. [38] Prasad B, Evers R, Gupta A, Hop CE, Salphati L, Shukla S, et al. Interindividual variability in hepatic organic anion-transporting polypeptides and P-glycoprotein (ABCB1) protein expression: quantification by liquid chromatography tandem mass spectroscopy and influence of genotype, age, and sex. Drug Metab Dispos 2014;42:78e88. [39] Rebello S, Zhao S, Hariry S, Dahlke M, Alexander N, Vapurcuyan A, et al. Intestinal OATP1A2 inhibition as a potential mechanism for the effect of grapefruit juice on aliskiren pharmacokinetics in healthy subjects. Eur J Clin Pharmacol 2012;68:697e708.
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Regular article
The change of pharmacokinetics of fexofenadine enantiomers through the single and simultaneous grapefruit juice ingestion Q3
Yumiko Akamine a, Masatomo Miura a, *, Hisakazu Komori b, Ikumi Tamai b, Ichiro Ieiri c, Norio Yasui-Furukori d, Tsukasa Uno e a
Department of Pharmacy, Akita University Hospital, Akita, Japan Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan d Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki, Japan e Department of Pharmacy, Zikeikai-Aoimori Hospital, Aomori, Japan b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 3 April 2015 Received in revised form 3 June 2015 Accepted 19 June 2015 Available online xxx
The stereoselective pharmacokinetics of fexofenadine are associated with OATP2B1-mediated transport, and grapefruit juice (GFJ) is an inhibitor of OATP2B1. Therefore, in this study, we aimed to investigate whether and to what extent GFJ ingestion affected the pharmacokinetics of fexofenadine enantiomers in healthy subjects. In a randomized, two-phase, open-label, crossover study, 14 subjects received 60 mg of racemic fexofenadine simultaneously with water or GFJ. Ingestion of GFJ significantly decreased the areas under the plasma concentration-time curve (AUC0e24) for (R)- and (S)-fexofenadine by 39% and 52%, respectively. Subsequently, GFJ increased the mean R/S ratio of the AUC0e24 from 1.58 to 1.96 (P < 0.05). Although GFJ greatly reduced the amounts of (R)- and (S)-fexofenadine excreted into the urine (Ae0e24) by 52% and 61%, respectively, the mean R/S ratios of Ae0e24 and the renal clearances of both enantiomers were unchanged between the control and GFJ phases. GFJ, an OATP2B1 inhibitor, significantly reduced the plasma concentrations of fexofenadine enantiomers, exhibiting clinically moderate effects. The present results suggested that changes in OATP2B1 activity by GFJ may alter the stereoselective pharmacokinetics of fexofenadine and that reduced intestinal OATP2B1 activity may affect the stereoselectivity of fexofenadine.
Keywords: Enantiomer Fexofenadine Grapefruit juice OATP2B1 Pharmacokinetics
Q1
Copyright © 2015, Published by Elsevier Ltd on behalf of The Japanese Society for the Study of Xenobiotics.
1. Introduction Drugedrug interactions can occur through various drug transporters, and such interactions may cause substantial changes in the pharmacokinetics of orally administered drugs [1e3]. Similarly, studies have suggested that the mechanisms of foodedrug interactions may be related to the activities of several drug transporters [4,5]. In particular, grapefruit juice (GFJ) has been shown to have multiple interactions with many drugs, leading to increased side effects or loss of therapeutic effects [6,7]. Since GFJ has multiple inhibitory effects on drug transport and metabolic systems, complex GFJ-drug interactions have been observed [6e8]. For example, GFJ significantly increases the bioavailability of calcium
* Corresponding author. Akita University Hospital, Akita 010-8543, Japan. Tel.: þ81 18 884 6310; fax: þ81 18 836 2628. E-mail address: [email protected] (M. Miura).
channel blockers, immunosuppressants, and anticancer agents (molecular targeted drugs) [6]. The primary drug-interaction mechanisms are likely caused by the inhibition of intestinal cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp) [6,9,10]. Since CYP3A substrates overlap considerably with P-gp substrates [11], the inhibitory effects of GFJ may occur through the combination of CYP3A and P-gp. Additionally, GFJ causes decreased exposure to several drugs because GFJ inhibits organic anion-transporting polypeptides (OATPs), i.e., OATP1A2 and e2B1 [12e15]. GFJ decreases the oral bioavailability of OATP1A2 and/or OATP2B1 substrate drugs, such as fexofenadine, aliskiren, celiprolol, talinolol, and ciprofloxacine. OATP1A2 and OATP2B1 are expressed on the luminal membrane of small intestinal enterocytes and potentially participate in the active absorption of drugs [12,16e19]. Interestingly, the expression level of OATP2B1 is relatively higher than that of OATP1A2 [20,21]. Previous reports have shown that OATP2B1 mRNA levels are expressed in all intestinal sections (e.g., 0.06 for the ileum and
http://dx.doi.org/10.1016/j.dmpk.2015.06.005 1347-4367/Copyright © 2015, Published by Elsevier Ltd on behalf of The Japanese Society for the Study of Xenobiotics.
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0.02 for the duodenum and colon ascendens; the numbers represent copy numbers relative to that in the villin, with significantly increased expression when the number is larger than 0.01). In contrast, OATP1A2 mRNA is not detectable or expressed at negligible levels in all intestinal sections (e.g., 0.003 for the ileum, 0.0002 for the duodenum, and 0.0004 for the colon ascendens) [22]. Similarly, other reports have shown that OATP2B1 protein is expressed in the small intestine in humans, while OATP1A2 protein could not be detected [20]. Taken together, these data show that OATP2B1 is the predominantly expressed isoform in the intestine and may be responsible for the observed OATP function in the small intestine. Therefore, although the contribution of OATP1A2 to GFJ-drug interactions cannot be ruled out, OATP2B1 may be the key determinant of intestinal OATP-mediated transport. Characterization of fexofenadine enantiomers after racemic dosing indicates the occurrence of stereoselectivity; the plasma concentration of (R)-fexofenadine is approximately 1.5-fold higher than that of the (S)-enantiomer [23,24]. These pharmacokinetics primarily depend on the activities of multiple transporters, including P-gp and OATPs [25]. Previous human studies have revealed that P-gp inhibitors, such as itraconazole and verapamil, significantly increase the concentrations of both enantiomers through inhibition of the efflux activity of intestinal Pgp [26,27]. In contrast, our recent report indicated that polymorphisms in the SLCO gene, which encodes OATP, are more highly associated with the pharmacokinetics of fexofenadine enantiomers than polymorphisms in the ABCB1 gene (also known as MDR1), which encodes P-gp [28]. In addition, rifampicin is a potent P-gp inducer and OATP inhibitor and has been shown to cause a marked increase in the concentrations of both enantiomers of fexofenadine [29,30]. These results suggested that rifampicin may inhibit the OATP-mediated transport of both enantiomers in the liver, and this effect may be greater than the induction effect on P-gp. In addition, these results imply that the drug and food interactions of fexofenadine occurring through OATP-mediated transport are likely to exhibit different effects in the intestine and liver. To date, the differences in the pharmacological effects and safety profiles of fexofenadine enantiomers have not been fully established. Although Robbins et al. reported that the two enantiomers are pharmacologically identical [23], our recent in vitro binding assays demonstrated that (S)-fexofenadine is a more potent human histamine H1 receptor antagonist than (R)-fexofenadine [30]. Therefore, (S)-fexofenadine shows larger receptor occupancy and consequently makes a greater contribution to the pharmacological response than (R)-fexofenadine. Moreover, our most recent study indicated that apple juice (AJ) significantly decreases the oral bioavailability of both fexofenadine enantiomers [31]. In an in vitro uptake study, the uptake of both fexofenadine enantiomers into oocytes injected with OATP2B1 cRNA is significantly higher than that into oocytes injected with water, and this effect is greater for (R)-fexofenadine [31]. In addition, AJ significantly decreases the uptake of both enantiomers into oocytes injected with OATP2B1 cRNA [31]. Furthermore, we have shown that the uptake of both enantiomers is the same in P-gp-, OATP1B3-, OAT3-, and multidrug and toxic compound extrusion 1 (MATE1)-expressing cells [30]. Thus, these results suggest that OATP2B1 may be the main factor mediating the stereoselectivity of fexofenadine and fexofenadine enantiomer pharmacokinetics. To date, no reports have examined the effects of GFJ on the stereoselectivity of co-administered drugs. Therefore, this study was designed to examine whether and to what extent GFJ, administered once orally, affected the pharmacokinetics of fexofenadine enantiomers.
2. Methods 2.1. Subjects Most of the 14 healthy Japanese volunteers (11 men and 3 women) who were included in this study had participated in our previous study [28]. Each subject was deemed physically healthy by a clinical examination and routine laboratory testing and had no history of significant medical illnesses or hypersensitivity to any drugs. The volunteers had a mean (±SD) age of 25.0 (±4.9) years and a mean body weight of 57.6 (±7.5) kg. This study was approved by the Ethics Committee of the Hirosaki University School of Medicine, and all subjects gave written informed consent before participating. 2.2. Study design A randomized crossover study design in two phases was conducted in intervals of at least 2 weeks. Following an overnight fast, healthy subjects simultaneously received 60 mg of racemic fexofenadine hydrochloride (Allegra; Sanofi K.K., Tokyo, Japan) with 250 mL of water or GFJ at 9:00 AM. The extract from tablets (Allegra) did not have optical activity; as a result, fexofenadine was administered as a racemic mixture, i.e. a 50/50 mixture of enantiomers, where the dose was 30 mg for each fexofenadine enantiomer. The GFJ (Tropicana; Kirin Beverage Co. Ltd., Tokyo, Japan) used in this study was of normal strength. Volunteers did not ingest any medication, fruit juices, or grapefruit, orange, or grapefruit products for at least 7 days before either of the study phases. No meals or beverages were allowed until 4 h after fexofenadine administration. In addition, the use of alcohol, tea, and coffee was forbidden during the test period. 2.3. Plasma and urine collection and determination of fexofenadine enantiomer concentrations Blood samples (10 mL each) were drawn into heparinized tubes before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 h after administration of fexofenadine, and the plasma was immediately separated. Immediately prior to fexofenadine administration, urine was collected to provide a blank sample. After fexofenadine administration, urine samples were collected during the subsequent 24-h period. Plasma and urine samples were stored at 20 C until assayed. Fexofenadine concentrations in plasma and urine were determined using a high-performance liquid chromatography (HPLC) method that had been developed in our laboratory [32]. In brief, following the addition of diphenhydramine (50 ng) in methanol (10 mL) as an internal standard to 400 mL of plasma, the plasma sample was diluted with 600 mL water and was vortexed for 30 s. For urine samples, diphenhydramine (50 ng) in methanol (10 mL) was added to 100 mL urine, and the sample was then diluted with 900 mL water. These sample mixtures were applied to an Oasis HLB extraction cartridge that had been previously activated with methanol and water (1.0 mL each). The cartridge was successively washed with 1.0 mL of water and 1.0 mL of 40% methanol in water followed by elution with 1.0 mL of 100% methanol. Eluates were evaporated to dryness under vacuum at 40 C using a rotary evaporator (Iwaki, Tokyo, Japan). The residue was dissolved in 50 mL methanol and was vortexed for 30 s. Approximately 50 mL of the mobile phase was added, and the sample was vortexed for another 30 s. A 50-mL aliquot of the sample was then processed using the HPLC apparatus. The HPLC column was a Chiral CD-Ph (250 mm 4.6 mm i.d.; Shiseido, Tokyo, Japan), and the mobile phase was 0.5% KH2PO4 (pH 3.5)-acetonitrile (65:35, v:v). The flow rate was 0.5 mL/min at ambient temperature, and sample
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detection was performed at 220 nm. The lower limit of quantification was 25 ng/mL for both (R)- and (S)-fexofenadine, and the limit of detection was 12.5 ng/mL for each enantiomer of fexofenadine. The validated concentration range of this assay for plasma and urine samples was 25e625 ng/mL for both enantiomers. The within- and between-day coefficients of variation were less than 13.6%, and accuracy was within 8.8% over the linear range of both analytes. The plasma and urine samples after GFJ treatment did not have any interfering peaks in the fexofenadine assay. The plasma and urine blank samples that were collected before fexofenadine administration presented no detectable fexofenadine peak in the assay.
3
figures. Differences in the pharmacokinetic parameters between (R)- and (S)-fexofenadine and between the control phase and the treatment phase as well as in the R/S ratio of the AUC0e24, Ae0e24, and CLrenal between the control phase and the treatment phase were analyzed using paired t-tests. Statistical analysis was performed using SPSS version 20.0 for Windows (SPSS, IBM Japan Inc., Tokyo, Japan) and WinNonlin (Version 5.2; Pharsight Co., Mountain View, CA, USA). Differences with P-values of less than 0.05 were considered statistically significant. 3. Results 3.1. Plasma pharmacokinetics of fexofenadine enantiomers
2.4. Pharmacokinetic data analysis Pharmacokinetic analysis of fexofenadine enantiomers was performed with a standard, noncompartmental method using WinNonlin (Pharsight Co., Mountain View, CA, Version 4.0.1). The maximum plasma concentration (Cmax) and time to reach Cmax (tmax) were determined directly from the observed data. The elimination rate constant (ke) for fexofenadine was obtained by linear regression analysis using at least 3 sampling points from the terminal log-linear declining phase to the last measurable concentration. The elimination half-life (t1/2) was calculated as 0.693 divided by ke. The AUC from time zero to the last sampling time (AUC0e24) was calculated by the trapezoidal rule. The apparent oral clearance (CL/F) was obtained from the equation CL/F ¼ Dose/ AUC0e24, where the Dose was 30 mg for each fexofenadine enantiomer. Renal clearance (CLrenal) was obtained from the following equation: CLrenal ¼ Ae0e24/AUC0e24, where Ae is the amount of fexofenadine excreted into the urine within a 24-h period. 2.5. Statistical analysis The results are expressed as the mean and 95% confidence interval (CI) in the table or the mean þ standard deviation (SD) in the
None of the enrolled subjects reported any adverse events during the study, and the subjects completed all phases according to the study protocol. The mean (þSD) plasma concentration-time profiles of the fexofenadine enantiomers after a single oral dose of 60 mg of fexofenadine hydrochloride are shown in Fig. 1 for both the control (water) and GFJ-treated phases. The pharmacokinetic parameters are summarized in Table 1. Single ingestion of GFJ greatly reduced the plasma concentrations of both fexofenadine enantiomers compared with those from the water phase (Figs. 2 and 3). GFJ also altered all of the pharmacokinetic parameters except t1/2 and tmax (Table 1). On the other hand, in the water phase, the plasma concentration of (R)-fexofenadine at all time points was higher than that of the corresponding (S)-enantiomer, and the mean AUC0e24 R/S ratio was 1.58 (95% CI, 1.36e1.81; Fig. 1 and Table 1). GFJ significantly decreased the AUC0e24 values of both enantiomers in all subjects except one (P < 0.001 for both enantiomers; Fig. 2). Additionally, these effects were dependent on the baseline value of each enantiomer, and a highly significant correlation was observed (R2 ¼ 0.7169, P < 0.001 for (R)-fexofenadine; R2 ¼ 0.9300, P < 0.001 for (S)-fexofenadine; Fig. 3). GFJ increased the mean R/S ratio of the AUC0e24 from 1.58 to 1.96 (95% CI, 1.65e2.27; P < 0.05; Table 1).
B (S)-foxofenadine concentration (ng/mL)
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Fig. 1. A: Mean (þSD) plasma concentration-time curves of (R)-fexofenadine following a single oral administration of 60 mg fexofenadine hydrochloride in 14 healthy volunteers treated with water (open squares) or GFJ (closed squares). B: Mean (þSD) plasma concentration-time curves of (S)-fexofenadine following a single oral administration of 60 mg fexofenadine hydrochloride in 14 healthy volunteers treated with water (open circles) or GFJ (closed circles).
Please cite this article in press as: Akamine Y, et al., The change of pharmacokinetics of fexofenadine enantiomers through the single and simultaneous grapefruit juice ingestion, Drug Metabolism and Pharmacokinetics (2015), http://dx.doi.org/10.1016/j.dmpk.2015.06.005
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Table 1 Effect of GFJ on pharmacokinetic parameters of fexofenadine enantiomers.
(R)-fexofenadine
(S)-fexofenadine
Parameters
control
＋GFJ
Ratio to control
t1/2 (h) tmax (h) (range) Cmax (ng/mL) AUC0e24 (ng･h/mL) CL/F (L/h) Ae0e24 (mg) CLrenal (L/h) t1/2 (h) tmax (h) (range) Cmax (ng/mL) AUC0e24 (ng･h/mL) CL/F (L/h) Ae0e24 (mg) CLrenal (L/h)
4.0 (3.4e4.6) 1.4 (0.5e3.0) 131 (111e151) 777 (660e893) 41 (36e47) 3.2 (2.4e4.1) 4.5 (3.2e5.7) 3.3 (2.9e3.8)y 1.5 (0.5e4.0) 110 (93e126)yyy 562 (427e697)yyy 62 (50e74)yyy 4.0 (3.1e4.8) 8.4 (6.4e10.4)yyy 1.58 (1.36e1.81) 0.61 (0.42e0.80)
4.3 (3.7e4.9) 2.0 (1.0e4.0) 68 (54e81)*** 461 (353e569)*** 75 (61e88)*** 1.4 (0.9e1.8)** 3.4 (2.1e4.7) 3.5 (3.1e4.0)yy 2.1 (1.0e4.0) 45 (34e55)***yyy 244 (178e309)***yyy 143 (117e169)***yyy 1.4 (1.0e2.0)*** 6.5 (4.4e8.7)yyy 1.96 (1.65e2.27)* 0.50 (0.45e0.55)
1.20 1.84 0.55 0.61 1.86 0.48 0.88 1.21 1.92 0.44 0.48 2.56 0.39 0.78 1.39 1.06
R/S ratio of AUC R/S ratio of CLrenal
(0.90e1.50) (1.03e2.64) (0.44e0.67) (0.48e0.74) (1.52e2.20) (0.33e0.63) (0.55e1.22) (0.95e1.48) (1.07e2.77) (0.33e0.54) (0.35e0.61) (1.92e3.22) (0.27e0.52) (0.40e1.16) (1.09e1.69) (0.74e1.39)
*P < 0.05, **P < 0.01, ***P < 0.001, between control phase and GFJ phase. yP < 0.05, yyP < 0.01, yyyP < 0.001, between (R)-fexofenadine and (S)-fexofenadine. Data are shown as mean and 95% confidence interval; tmax data are shown as a median with a range.
3.2. Urinary excretion of fexofenadine enantiomers In the control phase, the Ae0e24 of (S)-fexofenadine was slightly higher than that of (R)-fexofenadine; however, the difference did not reach statistical significance (P ¼ 0.266; Fig. 4). The mean CLrenal of (S)-fexofenadine was significantly higher than that of (R)-fexofenadine (P < 0.001; Table 1). GFJ greatly decreased the mean Ae0e24 values of both enantiomers (P < 0.01 for the (R)-enantiomer, P < 0.001 for the (S)-enantiomer; Fig. 4 and Table 1). In addition, compared to the control, GFJ did not change the mean CLrenal of either enantiomer. GFJ slightly decreased the mean R/S ratio of the CLrenal from 0.61 (95% CI, 0.42e0.80) to 0.50 (95% CI, 0.45e0.55), but this difference was not statistically significant (P ¼ 0.293; Table 1). 4. Discussion In this study, we investigated the effects of a single ingestion of GFJ on the pharmacokinetics of fexofenadine enantiomers. The results showed that GFJ significantly decreased the mean Cmax and
AUC0e24 of both enantiomers, even after only a single ingestion (Figs. 1 and 2). No significant differences were shown in pharmacokinetic parameters involving tmax, t1/2, and CLrenal between the control and GFJ phases (Table 1). If this effect of GFJ could be attributed to inhibition of hepatic OATP-mediated transport, the plasma concentrations of both enantiomers would have been somewhat enhanced, as described previously [1e3]. In addition, recent studies have found that OATP2B1 is a major OATPtransporter in the small intestine and that the uptake/transport of fexofenadine in oocytes injected with OATP2B1 cRNA is significantly decreased in the presence of GFJ [15,33,34]. Therefore, these results suggested that GFJ inhibited the intestinal OATP2B1mediated transport of fexofenadine enantiomers and may alter the pharmacokinetics of both enantiomers. Additionally, a previous clinical study found that a single ingestion of AJ significantly decreases the AUC0e24 for (R)- and (S)fexofenadine by 49% and 59%, respectively [31], while the present single-intake GFJ study showed that the AUC0e24 values of (R)- and (S)-fexofenadine decreased by 39% and 52%, respectively (Table 1). A recent in vitro study reported that co-incubation with AJ reduces
Fig. 2. A: Individual changes in the AUC0e24 of (R)-fexofenadine following a single oral administration of 60 mg fexofenadine hydrochloride in 14 healthy volunteers treated with water or GFJ. B: Individual changes in the AUC0e24 of (S)-fexofenadine following a single oral administration of 60 mg fexofenadine hydrochloride in 14 healthy volunteers treated with water or GFJ. ***P < 0.001, between control phase and GFJ phase.
Please cite this article in press as: Akamine Y, et al., The change of pharmacokinetics of fexofenadine enantiomers through the single and simultaneous grapefruit juice ingestion, Drug Metabolism and Pharmacokinetics (2015), http://dx.doi.org/10.1016/j.dmpk.2015.06.005
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differences between in vivo and in vitro results. However, the present study suggested that a single ingestion of GFJ could possibly be of moderate clinical significance for patients receiving OATP2B1 substrate drugs, such as fexofenadine. These findings imply that the inhibitory effects of GFJ were similar to or less than those of AJ. In our recent in vitro study [31], uptake into oocytes injected with OATP2B1 cRNA was higher for (R)-fexofenadine than (S)-fexofenadine. Consistent with these results, the present in vivo analysis demonstrated that the plasma concentration of (R)fexofenadine was higher than the corresponding (S)-enantiomer during the control phase (Fig. 1). In addition, in our former in vitro study, the stereoselectivity of fexofenadine enantiomer transport was not found in P-gp-, OATP1B3-, OAT3-, or MATE1-expressing cells [30]. Furthermore, OATP2B1 plays an important role in the hepatic disposition of substrate drugs [38]. Thus, if hepatic OATP2B1-mediated transport was a primary determinant of the stereoselective pharmacokinetics of fexofenadine, (R)-fexofenadine may be excreted primarily into the bile, and the plasma concentration of (S)-fexofenadine would be higher than the corresponding (R)-enantiomer. On the other hand, similar to previous studies, the Ae0e24 of (S)-fexofenadine was almost the same as that of (R)-fexofenadine during both the control and GFJ phases (Fig. 4). This result suggested that the urinary excretion of fexofenadine enantiomers was unlikely to be stereoselectivity because P-gp, OAT3, and MATE plays some roles in fexofenadine urinary excretion and those transporters disappear to demonstrate the stereoselectivity of fexofenadine enantiomers. These results strongly support that intestinal OATP2B1-mediated transport may be a crucial determinant of the stereoselective pharmacokinetics of fexofenadine enantiomers. In additive to the effect of OATP2B1, an in vivo and in vitro studies have been reported that OATP1A2 is contributed to the uptake of fexofenadine in the small intestine and that verapamil inhibited the uptake of fexofenadine through OATP1A2-mediated transport [39]. Unfortunately, in the present study, although the authors were not able to determine the effect to which OATP1A2 contributed to the stereoselectivity of fexofenadine in in vitro study using oocytes, our previous in vivo report showed that verapamil altered the stereoselectivity of fexofenadine [27]. Therefore, these findings may imply the potential that OATP1A2 takes part in the stereoselective pharmacokinetics of fexofenadine and GFJ inhibits both OATP1A2-and OATP2B1-mediated transports of fexofenadine enantiomers. However, to clarify these contributions to fexofenadine enantiomer pharmacokinetics, further in vivo and in vitro studies will be needed.
Fig. 3. Changes in the AUC0e24 values of (R)- and (S)-fexofenadine following ingestion of GFJ plotted against the AUC0e24 during the water phase for each individual (n ¼ 14). (R)-fexofenadine (open squares) and (S)-fexofenadine (closed circles).
the inhibitory effects of OATP2B1 [15]; the apparent half-maximal inhibitor concentrations (IC50) were in the order of GFJ < orange juice (OJ) < AJ, and the inhibitory effect of GFJ was most potent. However, the present results indicated that the GFJ-dependent reductions in plasma concentrations of fexofenadine enantiomers were similar to or less than those induced by AJ and that the inhibitory effects of AJ were greater than those of GFJ. These results are consistent with another in vivo report [12]. Furthermore, Shirasaka et al. reported that naringin, a component in GFJ, is the predominant molecule responsible for the inhibition of OATP2B1, while phloridzin and phloretin are the primary components contributing to inhibition of OATP2B1-mediated uptake in AJ [15]. Naringin has also been reported to inhibit P-gp [35,36], and P-gp significantly contributes to the pharmacokinetics of fexofenadine enantiomers [24,25,37]. Based on these previous studies, naringin in GFJ would be expected to inhibit both P-gp- and OATP2B1-mediated transport in relation to fexofenadine pharmacokinetics, and the reduced plasma concentrations of fexofenadine enantiomers in response to OATP2B1 inhibition may be attenuated by naringin-induced inhibition of P-gp, resulting in the observed
A
B 5 4
3 2 1 0 0
6
12
Time (h)
18
24
Ae0-24 of (S)-fexofenadine (mg)
Ae0-24 of (R)-fexofenadine (mg)
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5 4 3 2 1 0 0
6
12
18
24
Time (h)
Fig. 4. A: Mean (þSD) cumulative amount of (R)-fexofenadine excreted into the urine during water (open squares) or GFJ (closed squares) administration. B: Mean (þSD) cumulative amount of (S)-fexofenadine excreted into the urine during water (open circles) or GFJ (closed circles) ingestion.
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Additionally, a previous clinical study showed that single ingestion of AJ increased the mean R/S ratio of the AUC0e24 from 1.49 to 2.00 [31]. Similarly, the present single-intake GFJ study showed that the mean R/S ratio of the AUC0e24 increased significantly from 1.58 to 1.96 (Table 1). Furthermore, similar to the results of the AJ study [31], the inhibitory effects of GFJ on fexofenadine enantiomers were highly correlated with the baseline AUC0e24 value of each enantiomer; the more dramatic change in ratio following ingestion of GFJ may be due to the higher AUC0e24 value in the control (Fig. 3). Therefore, these results indicated that the inhibitory effects of AJ and GFJ on OATP2B1-mediated transport were similar, despite the differences in primary inhibitory components between the two juice types. Moreover, both juices are likely to have greater inhibitory effects on (S)-fexofenadine. Accordingly, these results imply that the concentration ranges of the main components in GFJ and AJ may be more sufficient for the inhibition of (S)-fexofenadine than for that of (R)-fexofenadine. However, further in vivo and in vitro studies will be required to elucidate the specific mechanism. In conclusion, the present study indicated that a single ingestion of GFJ could be of moderate clinical significance for patients receiving OATP2B1 substrate drugs, such as fexofenadine. Furthermore, our results suggested that changes in OATP2B1 activity in response to GFJ may alter the stereoselective pharmacokinetics of fexofenadine and that reduced intestinal OATP2B1 activity may affect the stereoselectivity of fexofenadine. Conflict of interest statement The authors have no conflicts of interest in relation to this paper. Acknowledgments We are very grateful to Prof. Hiroyuki Kusuhara (Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo) for providing grateful comments on this study. References [1] Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, Chu X, et al. Membrane transporters in drug development. Nat Rev Drug Discov 2010;9: 215e36. [2] Kalliokoski A, Niemi M. Impact of OATP transporters on pharmacokinetics. Br J Pharmacol 2009;158:693e705. [3] Shitara Y. Clinical importance of OATP1B1 and OATP1B3 in drug-drug interactions. Drug Metab Pharmacokinet 2011;26:220e7. [4] Bailey DG. Fruit juice inhibition of uptake transport: a new type of food-drug interaction. Br J Clin Pharmacol 2010;70:645e55. [5] Dolton MJ, Roufogalis BD, McLachlan AJ. Fruit juices as perpetrators of drug interactions: the role of organic anion-transporting polypeptides. Clin Pharmacol Ther 2012;92:622e30. [6] Seden K, Dickinson L, Khoo S, Back D. Grapefruit-drug interactions. Drugs 2010;70:2373e407. [7] Uno T, Yasui-Furukori N. Effect of grapefruit juice in relation to human pharmacokinetic study. Curr Clin Pharmacol 2006;1:157e61. [8] Rodriguez-Fragoso L, Martinez-Arismendi JL, Orozco-Bustos D, ReyesEsparza J, Torres E, Burchiel SW. Potential risks resulting from fruit/vegetabledrug interactions: effects on drug-metabolizing enzymes and drug transporters. J Food Sci 2011;76:R112e24. [9] Hanley MJ, Cancalon P, Widmer WW, Greenblatt DJ. The effect of grapefruit juice on drug disposition. Expert Opin Drug Metab Toxicol 2011;7: 267e86. [10] Bailey DG, Dresser GK. Interactions between grapefruit juice and cardiovascular drugs. Am J Cardiovasc Drugs 2004;4:281e97. [11] Zhou SF. Drugs behave as substrates, inhibitors and inducers of human cytochrome P450 3A4. Curr Drug Metab 2008;9:310e22. [12] Dresser GK, Bailey DG, Leake BF, Schwarz UI, Dawson PA, Freeman DJ, et al. Fruit juices inhibit organic anion transporting polypeptide-mediated drug uptake to decrease the oral availability of fexofenadine. Clin Pharmacol Ther 2002;71:11e20.
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