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

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1 DOI: /j x British Journal of Clinical Pharmacology Effect of grapefruit juice on the disposition of manidipine enantiomers in healthy subjects Tsukasa Uno, 1,3 Tadashi Ohkubo, 2 Shigeru Motomura 4 & Kazunobu Sugawara 1 1 Department of Pharmacy and 2 Clinical Research Centre, Hirosaki University Hospital, and 3 Department of Clinical Pharmacology and 4 Department of Pharmacology, Hirosaki University School of Medicine, Hirosaki, Japan Correspondence Tsukasa Uno PhD, Department of Clinical Pharmacology, Hirosaki University School of Medicine, Hirosaki , Japan. Tel: Fax: uno-hki@umin.ac.jp Keywords CYP3A4, enantiomer, grapefruit juice, manidipine Received 26 June 2005 Accepted 13 November 2005 Published OnlineEarly 2 February 2006 Aim To examine the effect of grapefruit juice, an inhibitor of CYP3A4 in the small intestine, on the disposition of manidipine enantiomers in healthy subjects. Methods A randomized cross-over study with at least a 2-week wash-out period was performed. Seven healthy male volunteers received an oral 40-mg dose of racemic manidipine after an overnight fast with either grapefruit juice (GFJ) or water, as a control study. Plasma concentrations of (S)- and (R)-manidipine were monitored up to 10 h after the dosing. Results The plasma concentrations of (S)-manidipine were significantly higher (P < 0.001) than those of (R)-manidipine in the control phase with an S/R ratio for the AUC 0 of 1.62 (95% confidence interval 1.52, 1.73). GFJ significantly increased C max and AUC 0 of (S)-manidipine by 2.4-fold (P < 0.01) and 2.3-fold (P < 0.01), respectively, and C max and AUC 0 of (R)-manidipine were increased by 3.4-fold (P < 0.01) and 3.0-fold (P < 0.01), respectively. There were significant differences (P < 0.01) in GFJmediated percentage increases in C max and AUC 0 of (S)-manidipine compared with those of (R)-manidipine. The S/R ratio for AUC 0 was significantly decreased from 1.6 to 1.2 during the GFJ phase (P < 0.01). Conclusion These results indicate that the stereoselective disposition of manidipine was altered by GFJ, as an inhibitor of CYP3A4. GFJ appears to affect this metabolic disposal of (R)-manidipine to a greater extent than that of (S)-manidipine. Introduction Grapefruit juice (GFJ) interacts with a number of drugs and can alter their pharmacokinetic and pharmacodynamic parameters. As for these interactions, most reports have focused on the elevation of drug bioavailability by GFJ [1], but some recent reports have indicated that GFJ reduced the absorption of drugs not metabolized by cytochrome P450 (CYP) [2]. The predominant mechanism for these interactions may be considered the net effect on drug disposition resulting in a combination of intestinal CYP3A4 and OATP1A2 inhibition [2, 3]. The action of GFJ is rapid and a single exposure to one glass of the juice can usually produce a significant interaction [4]. Moreover, there are dosedependent [5] and time-dependent [6] effects of GFJ on CYP3A. Manidipine is a potent 1,4-dihydropyridine calcium (Ca)-antagonist having long-lasting activity [7] and is prescribed for patients with mild-to-moderate hypertension [8]. The pharmacological effects of manidipine 2006 The Authors Br J Clin Pharmacol 61: Journal compilation 2006 Blackwell Publishing Ltd

2 T. Uno et al. enantiomers are known to be different and the pharmacological potency of (S)-manidipine has been found to be greater than that of (R)-manidipine [9]. Similarly, the pharmacokinetics of manidipine enantiomers are known to be markedly different and the S/R ratio for (S)- and (R)-enantiomer concentrations was 2.0 [10]. Generally, it is known that 1,4-dihydropyridine Caantagonists are metabolized by CYP3A4 in the human liver [11] and intestine [3], although there is no information about the stereoselective metabolism of manidipine enantiomers. GFJ, a potent CYP3A4 inhibitor, augmented the oral bioavailability of many 1,4-dihydropyridine Caantagonists, including felodipine, which was the first drug reported to be affected by GFJ [12]. However, there is no published information indicating a detailed pharmacokinetic drug interaction between GFJ and manidipine. This study was therefore designed to examine whether GFJ would really affect the pharmacokinetics of manidipine enantiomers and to determine to what extent GFJ affects the pharmacokinetics of each enantiomer of manidipine. Methods Study design Seven healthy Japanese male volunteers were enrolled in this study. Their mean age was 30.1 ± 7.1 years and mean body weight was 59.6 ± 5.4 kg. The Ethics Committee of Hirosaki University School of Medicine approved the study protocol and written informed consent was obtained from each participant before any examinations. A randomized, cross-over study design in two phases was conducted at intervals of at least 2 weeks. All subjects ingested either 250 ml water or 250 ml GFJ (Japan Agricultural Brand, Tokyo, Japan) at h. Thereafter, they took 40 mg of racemic manidipine (two 20-mg tablets, CALSLOT ; Takeda Pharmaceutical Co., Ltd, Osaka, Japan) at h with 200 ml water. No other medications were taken during the study periods. No meal was allowed until 4 h after the dosing (13.00 h). The use of alcohol, tea, coffee and cola was forbidden during the test days. Ingestions of GFJ were not allowed at least 1 week before the test day in both phases. Blood samplings Blood samples (10 ml each) for determination of manidipine enantiomers were taken into heparinized tubes just before and 0.5, 1, 2, 3, 4, 6, 8 and 10 h after the administration of manidipine. Plasma was separated immediately and kept at 30 C until analysis. Assay Plasma (S)- and (R)-manidipine concentrations were measured with a high-performance liquid chromatographic (HPLC) method developed at our laboratory [13]. (+)-Barnidipine (20 ng) in methanol (10 µl) was added to the plasma sample (1 ml) as an internal standard. The plasma sample was diluted with 5 ml of 1 mol l 1 sodium chloride solution and the solution was briefly mixed. The mixture was applied to a Bond Elut C 8 cartridge (Varian, Harbor City, CA, USA) and the cartridge was washed with 10 ml of water and 10 ml of 40% methanol. The fraction desired was eluted with 5 ml of 80% methanol. The elution was evaporated to dryness in a vacuum at 60 C. The residue was dissolved in 0.2 ml of chloroform and the sample was injected into the HPLC system consisting of a Rheodyne Model 7120 injector (Rheodyne, Cotati, CA, USA). Another Rheodyne Model 7120 injector was used as a switching valve (Rheodyne). The HPLC precolumn contained a trimethylsilylated silica stationary phase (5 µm, mm i.d.) which was prepared in our laboratory and packed by a low-pressure packing technique. The analytical column contained a SUMICHIRAL OA-4500 chiral stationary phase (5 µm, mm i.d.) (Sumika Chemical Analysis Service, Osaka, Japan). A pump (PU-880; Jasco, Tokyo, Japan) was used with an ultraviolet detector (Uvidec 980; Jasco) set at a wavelength of 254 nm. The mobile phase consisted of n-hexane- 1,2-dichloroethane-methanol-trifluoroacetic acid (250 : 140 : 12 : 1, v/v), and the flow rate was 1 ml min 1 at ambient temperature. The limit of quantification was 1 ng ml 1 for (S)- and (R)-manidipine, respectively. The within-day and between-day coefficients of variation were <9.4% for both manidipine enantiomers. Data analyses of pharmacokinetics The peak concentration (C max ) and concentration peak time (t max ) were obtained directly from the original data. The AUC 0 10 was calculated with use of the trapezoidal rule. The terminal rate constant (k e ) used for the extrapolation was determined by regression analysis of the log-linear part of the concentration time curve for each subject. The elimination half-life was determined by 0.693/k e. Total AUC was calculated by AUC C10/ k e, where C10 is plasma drug concentration at 24 h after the administration. Total clearance (CL/F) was calculated by dose/auc 0. Statistical analyses Differences in pharmacokinetic parameters between (S)- and (R)-manidipine, between control phase and GFJ phase, and in GFJ-mediated percentage increase :5 Br J Clin Pharmacol

3 Grapefruit juice increased the plasma concentration of manidipine enantiomers between (S)- and (R)-manidipine in C max and the AUC 0 were analysed by the paired Student s t-test. A P-value of <0.05 was considered to be statistically significant. Statistical analyses were performed using by Stat View program (SAS Institute, Cary, NC, USA; version 5.0). To demonstrate a difference in AUC of 50% between two phases with an α error of 5% and a test power of 80%, the sample size required six subjects assuming the coefficient of variation of 30% based on the pharmacokinetics of our previous study [13]. Results Although none of the subjects needed to withdraw from this study, mild to moderate adverse events were observed during the two phases: mild to moderate headache (one and four subjects during the control and GFJ phase, respectively), mild flushing (one and three subjects during the control and GFJ phase, respectively) and mild palpitations (one and three subjects during the control and GFJ phase, respectively). These side-effects ameliorated around 6 h after dosing in both phases. Figure 1 Plasma concentration time curves of (S)- manidipine ( ) and (R)-manidipine ( ) after an oral 40-mg dose of racemic manidipine with water 250 ml (left panel) or grapefruit juice (GFJ) 250 ml (right panel). Data are shown as mean ± SD Manidipine concentration (ng/ml) Water Manidipine concentration (ng/ml) GFJ Time (hrs) Time (hrs) Table l Pharmacokinetic parameters of (S)- and (R)-manidipine (for each dose of 20 mg) after an oral administration of 40 mg racemic manidipine with water 250 ml or grapefruit juice (GFJ) 250 ml in seven healthy volunteers Parameters Water (S)-Manidipine (R)-Manidipine GFJ (S)-Manidipine (R)-Manidipine C max (ng ml 1 ) 9.4 (7.9, 10.8)** 5.4 (4.5, 6.2) 22.6 (16.8, 28.3)** 18.3 (13.6, 23.1) 1 t max (h) 1.8 ( ) 1.8 ( ) 1.8 ( ) 1.5 ( ) Elimination half-life (h) 2.9 (2.0, 3.8) 28 (2.2, 3.4) 2.6 (1.8, 3.4) 2.7 (2.1, 3.3) AUC 0 (ng h 1 ml 1 ) 42.7 (36.5, 48.9)** 26.5 (22.0, 30.9) (73.5, 128.5)* 80.2 (66.7, 93.7) CL/F (l h 1 kg 1 ) 8.9 (7.7, 10.2)** 14.6 (12.1, 17.1) 3.9 (3.2, 4.7)* 4.7 (4.2, 5.4) S/R ratio C max (ng ml 1 ) 1.75 (1.65,1.85) 1.23 (1.20, 1.27) AUC (1.52, 1.73) 124 (1.10, 1.39) Data are shown as mean and 95% confidence interval. 1 t max is median (range). Cmax, Peak concentration; t max, time to C max ; AUC 0, area under plasma concentration time curve from 0 to infinity; CL/F, the total clearance/kg for each subject; S/R ratio of Cmax, Cmax for (S)-manidipine/Cmax for (R)-manidipine; S/R ratio of AUC 0, AUC 0 for (S)-manidipine/AUC 0 for (R)- manidipine. *P < 0.01 and **P < compared with (R)-manidipine. P < 0.01 and P < compared with water. Br J Clin Pharmacol 61:5 535

4 T. Uno et al. The mean plasma concentrations of (S)- and (R)- manidipine during control and GFJ experiments are shown in Figure 1 and their pharmacokinetic parameters are summarized in Table 1. During the control phase, the mean plasma concentrations of (S)-manidipine were higher than those of (R)-manidipine (Figure 1). Significant changes were found in C max (P < 0.001), AUC 0 (P < 0.001) and CL/F (P < 0.001) between different manidipine enantiomers (Table 1). GFJ significantly increased C max and AUC 0 of (S)- manidipine by 2.4-fold (P < 0.01) and 2.3-fold (P < 0.01), respectively, and C max and AUC 0 of (R)-manidipine were increased by 3.4-fold (P < 0.01) and 3.0-fold (P < 0.01), respectively. The S/R ratio for AUC 0 in the GFJ was reduced significantly compared with that in the water phase (P < 0.01) (Table 1). No significant differences were found in t max or elimination half-life of (S)- and (R)-manidipine between the two phases. In addition, the GFJ-mediated percentage increases in C max (P < 0.01) and AUC 0 were significantly greater (P < 0.01) for (R)-manidipine compared with those for (S)-manidipine. There were no significant differences in pharmacodynamic variables (e.g. arterial blood pressure and heart rate) between the two phases, which were recorded during the same blood sampling time period. Discussion The result of this study showed that GFJ increased C max and the AUC 0 of both (S)- and (R)-enantiomers of manidipine. No significant difference was found in elimination half-life of manidipine enantiomers between the two phases. This finding is in accordance with a nitrendipine-gfj study [14] and our nicardipine-gfj study [15]. Consequently, these results suggest that both enantiomers of manidipine were mainly metabolized by CYP3A4, and GFJ probably inhibited the CYP3A4- mediated metabolism of both enantiomers in the small intestine, because there was no effect on the elimination half-life, indicating there was little inhibition of hepatic CYP3A4 activity. The present study showed significant differences in the C max and the AUC 0 between manidipine enantiomers in the control phase. The relative values of the C max and the AUC 0 between (S)-manidipine and (R)- manidipine were 1.8 : 1 and 1.6 : 1, respectively. This is in line with previous studies [10, 13]. In the GFJ phase, however, the relative values of the C max and AUC 0 between (S)-manidipine and (R)-manidipine were reduced to 1.2 : 1 because GFJ increased the C max and the AUC 0 values of (R)-manidipine to a significantly greater extent compared with those of (S)-manidipine. These results therefore suggest that GFJ inhibited the CYP3A4-mediated metabolism of (R)-manidipine more intensely than that of (S)-manidipine. This phenomenon is in accordance with our nicardipine-gfj study [15]. However, further studies will still be required, since it is not known whether the contribution of CYP3A4 to the metabolism of manidipine differs between the two enantiomers. Additionally, judging from our present findings of greater inhibition by GFJ upon (R)-manidipine with less pharmacological potency, the clinical implications of the GFJ manidipine interaction may be limited, even though some subjects in our present study complained of mild to moderate adverse events in the GFJ phase. The results of our study have demonstrated that manidipine disposition was stereoselective and the GFJ elevated the disposition of manidipine enantiomers differently, with (R)-enantiomer affected more than (S)- enantiomer. Recent reports have indicated that GFJ reduced the absorption of fexofenadine, a drug not metabolized by CYP3A4 [2], through the inhibition of uptake by intestinal organic anion transporting polypeptide A (OATP-1A2). Hence, our results indicate that the predominant mechanism of manidipine GFJ interaction is mediated through CYP3A4 rather than OATP1A2. In conclusion, this study indicates that GFJ ingestion increases manidipine exposure, probably due to the reduced first-pass effect by inhibiting CYP3A4 activity, and increases the manidipine bioavailability. The manidipine disposition is stereoseletive and the effect of GFJ ingestion may be greater upon (R)-manidipine than (S)-manidipine. We thank Professor Tomonori Tateishi (Department of Clinical Pharmacology, Hirosaki University of Medicine) for meaningful advice in the Discussion section. None of the authors has any financial or other relationships that could lead to conflicts of interest. 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