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British Journal of Clinical Pharmacology logoLink to British Journal of Clinical Pharmacology
. 2014 Apr 22;77(5):821–830. doi: 10.1111/bcp.12236

The effect of Ginkgo biloba extracts on the pharmacokinetics and pharmacodynamics of cilostazol and its active metabolites in healthy Korean subjects

Ho-Sook Kim 1,2,†, Ga-young Kim 1,†, Chang-Woo Yeo 1,2,‡, Minkyung Oh 1, Jong-lyul Ghim 2, Ji-Hong Shon 1,2, Eun-Young Kim 2, Dong-Hyun Kim 1, Jae-Gook Shin 1,2,✉
PMCID: PMC4004402  PMID: 24001154

Abstract

AIMS

The primary objective of this study was to evaluate the effects of Ginkgo biloba extracts (GBE) on the pharmacokinetics of cilostazol and its metabolites. The secondary objective was to assess the effect of GBE on the pharmacodynamics of cilostazol.

METHODS

A randomized, double-blind, two-way crossover study was conducted with 34 healthy Korean subjects. All subjects were given an oral dose of cilostazol (100 mg) plus GBE (80 mg) or cilostazol (100 mg) plus placebo twice daily for 7 days. Plasma concentrations of cilostazol and its active metabolites (3,4-dehydrocilostazol and 4′-trans-hydroxycilostazol) were measured using liquid chromatography–tandem mass spectroscopy on day 7 for pharmacokinetic assessment. The adenosine diphosphate-induced platelet aggregation and bleeding time were measured at baseline and on day 7 for pharmacodynamic assessment.

RESULTS

The geometric mean ratios of area under the concentration–time curve for dosing interval for cilostazol plus GBE vs. cilostazol plus placebo were 0.96 (90% confidence interval, 0.89–1.03; P = 0.20) for cilostazol, 0.96 (90% confidence interval, 0.90–1.02; P = 0.30) for 3,4-dehydrocilostazol and 0.98 (90% confidence interval, 0.93–1.03; P = 0.47) for 4′-trans-hydroxycilostazol. The change of aggregation after administration of cilostazol plus GBE seemed to be 1.31 times higher compared with cilostazol plus placebo, without statistical significance (P = 0.20). There were no significant changes in bleeding times and adverse drug reactions between the treatments.

CONCLUSIONS

Co-administration of GBE showed no statistically significant effects on the pharmacokinetics of cilostazol in healthy subjects. A large cohort study with long-term follow-up may be needed to evaluate the possible pharmacodynamic interaction between cilostazol and GBE, given that there was a remarkable, but not statistically significant, increase in inhibition of platelet aggregation.

Keywords: cilostazol, Ginkgo biloba extracts, herb–drug interaction, pharmacodynamics, pharmacokinetics

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

  • Cilostazol is metabolized by the cytochrome P450 (CYP) 3A4 and CYP2C19.

  • Ginkgo biloba extract (GBE) is a herbal medicine that may induce CYP enzymes.

  • Pharmacokinetic and pharmacodynamic interactions in humans between cilostazol and GBE are poorly understood.

WHAT THIS STUDY ADDS

  • Ginkgo biloba extract was found to have no statistically significant effects on the pharmacokinetics or pharmacodynamics of cilostazol and its active metabolites in healthy subjects administered multiple doses.

  • Cilostazol and GBE may be co-administered without significant pharmacokinetic and pharmacodynamic interaction.

Introduction

Cilostazol is a selective inhibitor of cyclic AMP phosphodiesterase III and has both antiplatelet and vasodilatory effects. It is used for the treatment of intermittent claudication [1]. Cilostazol is also reported to prevent stroke and the occurrence of restenosis after coronary angioplasty and stenting [2,3]. Compared with aspirin and pentoxifylline, cilostazol is a more potent inhibitor of primary and secondary platelet aggregation induced by adenosine diphosphate (ADP) or adrenaline [4,5]. Some studies have shown that the addition of cilostazol to other antiplatelet agents, e.g. aspirin, inhibits platelet aggregation without prolonging the bleeding time [6,7]. Recently, compared with dual antiplatelet therapy (clopidogrel and aspirin), triple antiplatelet therapy including cilostazol has been reported to be associated with reduced risk of stent thrombosis and major adverse cardiac events [8,9].

Ginkgo biloba extracts (GBE) have been used in traditional Chinese herbal medicine to treat circulatory disorders [10]. A World Health Organization monograph describes the use of GBE for symptomatic treatment of mild-to-moderate cerebrovascular insufficiency, improvement of pain-free walking distance in patients with peripheral arterial occlusive disease and treatment of inner ear problems, such as tinnitus [11]. Ginkgo biloba extract has been approved and used for the treatment of the same three indications in Germany and Korea [10,12,13] and is a commonly used over-the-counter preparation in several countries, including the USA [10]. Ginkgo biloba extract topped the list of the seven best-selling herbal products in 1998, with retail sales of US $150 million in the US market [14]. Although some reports have suggested it is not effective [15–17], Ginkgo biloba extract is often prescribed or administered in combination with other drugs, such as antihypertensive agents, hypoglycaemic agents and antiplatelet agents, including cilostazol [18,19]. In particular, cilostazol and GBE are often co-prescribed in patients with atherosclerotic disease or pheripheral artery disease, including intermittent claudication.

Ginkgo biloba extract has been shown to induce the expression of the cytochrome P450 (CYP) enzymes, including CYP3A4, although this is controversial [20,21]. Cilostazol is metabolized via CYP enzymes into two major metabolites, namely 3,4-dehydrocilostazol, which has four to seven times increased activity compared with cilostazol, and 4′-trans-hydroxycilostazol, which has one-fifth the activity of cilostazol. 3,4-Dehydrocilostazol is produced by CYP3A4, and 4′-trans-hydroxycilostazol is produced mainly by CYP3A5 and CYP2C19 [22]. This suggests the possibility of pharmacokinetic interactions between GBE and cilostazol. The change of active metabolite exposure can also lead to a change in antiplatelet effects.

There has been no report on pharmacokinetic interactions between cilostazol and GBE in humans. Therefore, the primary objective of the present study was to evaluate the effect of GBE on the pharmacokinetics of cilostazol and its active metabolites in healthy Korean subjects. In addition, the effect of GBE on pharmacodynamics of cilostazol was assessed.

Methods

Study subjects

Healthy Korean men, aged 19–45 years, who had no clinically significant abnormalities in medical history, physical examinations, electrocardiograms or clinical laboratory measurements and who were within 15% of their ideal bodyweight according to Broca's formula, were eligible for inclusion.

Subjects were excluded if they had a history or evidence of hepatic, renal, gastrointestinal or haematological abnormalities, any other acute or chronic disease, any drug allergies, or if they were taking any medication that induces or inhibits drug-metabolizing enzymes. None of the subjects smoked tobacco or used any regular medication. No medications, herbal medicine, alcohol, citrus juice, grapefruit juice or beverages containing caffeine were permitted for 10 days prior to the study and for the duration of the study.

All subjects were advised about the risks and benefits of participation in this study and submitted written, signed and dated informed consent voluntarily prior to participation in the clinical trial. Studies were conducted in compliance with the principles outlined in the Declaration of Helsinki, and the study protocol and all amendments were approved by the Institutional Review Board of Inje University Busan Paik Hospital (IRB approval number: 08-040) and the Korea Food and Drug Administration.

Study design

This study was designed as a randomized, double-blind, two-way crossover study with a 2 week washout (Figure 1). All subjects were administered an oral dose of 100 mg cilostazol (Pletal®; Otsuka Pharmaceutical Co. Ltd, Tokyo, Japan) plus 80 mg GBE (Ginexin®; SK Chemical Co., Seoul, Korea) or 100 mg cilostazol plus placebo (identical excipients of Ginexin® except GBE ingredients; provided by SK Chemical Co.) twice daily, in the morning and evening at 12 h intervals, for 7 days. The dosing of cilostazol and GBE was selected based on the approved maximal dose for peripheral arterial occlusive disease, including intermittent claudication (e.g. in Germany and Korea) [13,23]. Seven day multiple dosing was considered to be enough to reach steady state, based on it being longer than five times the half-life of the plasma concentration (the half-life of cilostazol is 10.5 ± 4.4 h, 3,4-dehydrocilostazol 11.7 ± 3.8 h and 4′-trans-hydroxycilostazol 13.3 ± 4.8 h) [4]. To reduce potential food effects on the pharmacokinetics of cilostazol [24], the morning and evening doses were administered 30 min before breakfast and 2 h after dinner, respectively. The morning and evening doses on days 1–5 and the morning dose on day 6 were taken at home. All subjects reported to the investigator by using a mobile phone message service immediately after morning drug administration at home, and the investigator called all subjects to confirm the administration of the evening dose and to check on the occurrence of adverse events. On the afternoon of day 6, all subjects were admitted to the clinical trial centre, where they received the evening dose on day 6 and morning dose on day 7. The subjects remained at the centre for 48 h after the dose on day 7. Before taking the last dose of cilostazol with placebo or GBE, the subjects fasted overnight and continued fasting until a standardized lunch was served 4 h after drug administration on day 7. Subjects were administered the evening dose of only placebo or GBE on day 7.

Figure 1.

Figure 1

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Design of the two-way crossover study administered cilostazol 100 mg plus Ginkgo biloba extracts (GBE) 80 mg or cilostazol 100 mg plus placebo at each period with 2 weeks washout period. Abbreviations are as follows: PD, pharmacodynamics; PK, pharmacokinetics

Blood samples for pharmacokinetic assessments were obtained at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24, 36 and 48 h after administration of the last cilostazol dose. Plasma samples were transferred immediately to polyethylene tubes and stored at −80°C until shipped for analysis. Plasma samples were packed in dry ice and sent by overnight courier to the analytical laboratory (Seoul Pharma Laboratories, Seoul, South Korea). Blood samples were also collected to measure ADP-induced platelet aggregation and bleeding time (see ‘Pharmacodynamic measurements’ below). The platelet aggregation tests were performed at 6 and 7 h and the bleeding time test at 7 h after the last administration of cilostazol, at which time the potential maximal antiplatelet effects of cilostazol have been shown. To assess the baseline platelet aggregation and bleeding time before the drug administration, these tests were performed at same times on day −1.

Bioanalysis

The plasma concentrations of cilostazol, 3,4-dehydrocilostazol and 4′-trans-hydroxycilostazol were determined using a liquid chromatography–tandem mass spectroscopy (LC-MS/MS) method developed by Seoul Pharma Laboratories. The LC-MS/MS analysis was performed using a Quatrro premier XE triple quadrupole mass spectrometer (Waters, Milford, MA, USA) equipped with a Waters 2795 high-performance liquid chromatographic system (Waters). In brief, a 0.05 ml aliquot of plasma was spiked with an internal standard (10 μl at 1 μl ml−1 tiapiride), alkalinized with 50 μl of 1 m sodium hydroxide, and extracted with 2 ml of methyl tert-butyl ether and chloroform (8:2 v/v). After vortex mixing for 5 min and centrifuging at 3000g for 10 min, the organic layer was separated and evaporated to dryness under a flow of nitrogen gas. The residue was reconstituted with 200 μl of 50% acetonitrile, and a 5 μl aliquot was injected into the LC-MS/MS system. Chromatographic separation was performed on a Gemini C18 column (150 mm × 2.0 mm internal diameter, 3 μm particle size), with an isocratic mobile phase consisting of 1 mm ammonium acetate (pH 4.5) and acetonitrile (30:70 v/v), with a flow rate of 0.2 ml min−1. Detection and quantification were performed using a mass spectrometer in selected reaction-monitoring mode with positive electrospray ionization at m/z 370.0 → 288.1 for cilostazol, m/z 368.1 → 286.1 for 3,4-dehydrocilostazol, m/z 386.0 → 288.1 for 4′-trans-hydroxycilostazol and m/z 329.2 → 256.1 for the internal standard. The linear calibration curves were established in a concentration range of 5–5000 ng ml−1, with a lower limit of quantification of 5 ng ml−1 for all analytes (r2 = 0.9970 for cilostazol, r2 = 0.9985 for3,4-dehydrocilostazol and r2 = 0.9981 for 4′-trans-hydroxycilostazol). The coefficient of variation for the assay precision was <11.7%, and the accuracy was >94.5%. No relevant crosstalk and matrix effect were observed.

Pharmacodynamic measurements

Platelet aggregation was measured using a Chrono-log Lumi Aggregometer (model 700-4DR; Chrono-log, Havertown, PA, USA) equipped with the AggroLink software package and using a turbidometric method, as described previously, with a minor modification [25]. In brief, blood samples were collected into tubes containing 3.2% citrate and then inverted three to five times for gentle mixing. The blood samples were separated by centrifugation at 180g for 10 min, and the supernatant was collected as the platelet-rich plasma (PRP). The remaining blood was further separated by centrifugation at 2170g for 10 min, and this supernatant was collected as the platelet-poor plasma (PPP). The PRP (0.5 ml) was incubated at 37°C for 2 min, and ADP (10 μm) was added with stirring at 1200 r.p.m. Platelet aggregation was recorded for up to 5 min and expressed as the maximal percentage change of light transmission from baseline using the PRP as a reference.

Bleeding time was determined by Duke's method [26]. The skin was cleaned with alcohol, and a lancet was used to puncture the ear lobe. The puncture site was blotted with filter paper every 30 s until bleeding stopped, and the total time was recorded.

Safety

Adverse events were identified by asking subjects general health-related questions and by scheduled physical examinations throughout the study. Clinical laboratory evaluations (haematology, serum chemistry, urinalysis and blood aggregation tests) and physical examinations were performed on day −1 before dosing and at discharge from the clinical trial centre (48 h after last dose). Vital signs were measured on day −1 before dosing and at 6, 12, 24, 36 and 48 h after the last dose. Adverse events were monitored, and their severity, frequency and relationship with the treatment were recorded.

Pharmacokinetic and pharmacodynamic data analysis

The pharmacokinetic parameters of cilostazol and its active metabolites (3,4-dehydrocilostazol and 4′-trans-hydroxycilostazol) were calculated using WinNonlin® 6.1 (Pharsight Co., Mountain View, CA, USA). The maximal concentration at steady state (Css,max) and the time to Css,max (Tmax) of cilostazol and its active metabolites were obtained from time–concentration curves. The area under the concentration–time curve for the 12 h dosing interval at steady state (AUCτ) was calculated by the linear trapezoidal rule. Clearance at steady state (CL/F) was calculated as the cilostazol dose divided by AUCτ.

For the pharmacodynamic evaluation, we used the average of the two aggregation values at baseline (on day −1; the same times as 6 and 7 h after final cilostazol administration on day 7) and the two values after administration of the last dose (6 and 7 h on day 7), considering the variation in the measured values. The change in the degree of platelet aggregation between before (baseline) and after drug administration was calculated as follows:

graphic file with name bcp0077-0821-mu1.jpg

where A0 is the average value of platelet aggregation response at baseline and At the average value of platelet aggregation response after drug administration.

The bleeding time prolongation factor was calculated as the change in bleeding time between before and after drug administration, as follows:

graphic file with name bcp0077-0821-mu2.jpg

where BT0 is bleeding time at baseline and BTt is bleeding time after drug administration.

The safety of cilostazol plus GBE and cilostazol plus placebo was evaluated in terms of vital signs, clinical laboratory results and medical examinations. Adverse reactions were compared in terms of severity, frequency and relationship with the treatment.

Data and statistical analysis

Sample size calculation was based on a previous report on the pharmacokinetics of cilostazol after administration for 7 days [27]. Based on 29.6% of the coefficients of variation for AUCτ, to obtain a mean difference of AUCτ within the interval log 0.8 to log 1.25 at the 5% significance level (α) with 80% statistical power (1 – β), the minimal number of subjects required per group was calculated to be 16, for a total of 32 subjects.

Pharmacokinetic and pharmacodynamic data analyses used data from subjects who completed the study, while safety was evaluated using data from all subjects receiving cilostazol or GBE at least once.

Continuous variables were expressed as means ± SD. Geometric mean ratios of natural log-transformed AUCτ and Css,max, as well as arithmetic mean ratios of other pharmacokinetic parameters for cilostazol and its active metabolites when administered with/without GBE, were calculated along with estimated 90% confidence intervals (CIs). Log-transformed AUCτ and Css,max, other pharmacokinetic parameters and pharmacodynamic parameters, such as ΔAggregation and bleeding time prolongation factor, were analysed using a mixed-model analysis of variance with fixed effects for sequence, period and treatment and a random effect for subject within sequence. Other pharmacodynamic results, such as platelet aggregation and bleeding time, were compared using Wilcoxon's rank sum test after a normality test. Values of P < 0.05 were deemed to indicate statistical significance. All statistical analyses were performed using SAS version 9.2 (SAS Institute Inc., Cary, NC, USA).

Results

Subjects

A total of 39 subjects were enrolled, and 34 subjects completed the entire clinical trial process. One subject dropped out on day −1 because of an abnormal laboratory test result; three subjects withdrew informed consent (one subject before period 1 and two subjects after the completion of period 1); and one subject dropped out due to noncompliance during period 1. As such, data from 34 subjects were eligible for pharmacokinetic and pharmacodynamic data analysis, and data from 37 subjects taking the drug at least once for safety assessments. The mean age of completing subjects was 24.3 ± 2.5 years (range, 20–34); mean height, 174.9 ± 5.1 cm (range, 165–186); and mean weight, 70.6 ± 7.1 kg (range, 53.4–82.3).

Pharmacokinetics

The mean plasma concentration–time profiles of cilostazol, 3,4-dehydrocilostazol and 4′-trans-hydroxycilostazol with and without GBE are shown in Figure 2. The mean pharmacokinetic parameters and statistics are shown in Table 1.

Figure 2.

Figure 2

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Concentration–time profiles of cilostazol (A), 3,4-dehydrocilostazol (B) and 4′-trans-hydroxycilostazol (C) in plasma after administration of cilostazol 100 mg plus Ginkgo biloba extracts (GBE) 80 mg (•) or cilostazol 100 mg plus placebo (○) for 7 days in 34 healthy Korean subjects

Table 1.

Pharmacokinetic parameters of cilostazol and its active metabolites in plasma after administration of cilostazol 100 mg plus Ginkgo biloba extracts (GBE) 80 mg or cilostazol 100 mg plus placebo for 7 days in 34 healthy Korean subjects

Parameter Cilostazol + placebo Cilostazol + GBE Ratio (90% CI) P value
Cilostazol
 Css,max (ng ml−1) 1182.0 ± 345.1 1138.2 ± 266.4 0.98 (0.91–1.05)* 0.46
 Tmax (h) 2.5 (1–7) 2.5 (1.5–6) 1.30 (1.08–1.52) 0.34
 AUCτ (ng h ml−1) 8947.3 ± 2685.7 8446.8 ± 2040.4 0.96 (0.89–1.03)* 0.20
 CL/F (l h−1) 12.2 ± 3.8 12.6 ± 3.4 1.08 (0.99–1.16) 0.48
3,4-Dehydrocilostazol
 Css,max (ng ml−1) 374.6 ± 128.2 362.2 ± 121.5 0.97 (0.90–1.04)* 0.46
 Tmax (h) 3.5 (0–10) 3.5 (0.5–6) 1.15 (0.90–1.40) 0.55
 AUCτ (ng h ml−1) 3588.8 ± 1254.5 3443.3 ± 1234.1 0.96 (0.90–1.02)* 0.30
4′-Trans-hydroxycilostazol
 Css,max (ng ml−1) 168.4 ± 42.3 166.2 ± 47.7 0.98 (0.92–1.04)* 0.73
 Tmax (h) 3 (0–5) 3.5 (1–6) 1.38 (1.03–1.72) 0.18
 AUCτ (ng h ml−1) 1413.9 ± 371.4 1381.5 ± 351.9 0.98 (0.93–1.03)* 0.47
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The values for Tmax (h) are given as median (range) and the other values as mean ± standard deviation. Abbreviations are as follows: AUCτ, area under the concentration–time curve for a dosing interval at steady state; CI, confidence interval; CL/F, oral clearance; Css,max, maximal plasma concentration at steady state; Tmax, the time to Css,max.

*

Ratios for Css,max, and AUCτ are shown as the geometric mean ratio (cilostazol plus GBE vs. cilostazol plus placebo).

The pharmacokinetics of cilostazol, 3,4-dehydrocilostazol and 4′-trans-hydroxycilostazol were similar between the cilostazol plus placebo treatment and the cilostazol plus GBE treatment, with no clinically relevant changes in pharmacokinetic parameters of cilostazol and its metabolites. The geometric mean ratios of Css,max and AUCτ of cilostazol after cilostazol plus GBE and after cilostazol plus placebo were 0.98 (90% CI, 0.91–1.05; P = 0.46) and 0.96 (90% CI, 0.89–1.03; P = 0.20), respectively. The geometric mean ratios for Css,max and AUCτ of 3,4-dehydrocilostazol between the two treatments were 0.97 (90% CI, 0.90–1.04; P = 0.46) and 0.96 (90% CI, 0.90–1.02; P = 0.30), respectively. The geometric mean ratios for Css,max and AUCτ of 4′-trans-hydroxycilostazol between the two treatments were 0.98 (90% CI, 0.92–1.04; P = 0.73) and 0.98 (90% CI, 0.93–1.03; 0.47), respectively.

Pharmacodynamics

Adenosine diphosphate-induced platelet aggregation was significantly decreased after the administration of cilostazol plus placebo or GBE for 7 days compared with measurement taken before treatments (P < 0.001; Figure 3A). The change in aggregation (ΔAggregation) after administration of cilostazol plus GBE seemed to be 1.31 times higher compared with administration of cilostazol plus placebo, but it was not statistically significant (P = 0.20; Table 2).

Figure 3.

Figure 3

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Effects of cilostazol + placebo and cilostazol + Ginkgo biloba extracts (GBE) on ADP-induced platelet aggregation (%; A) and bleeding time (B). GBE: Ginkgo biloba extract

Table 2.

Pharmacodynamic parameters after 7 days administration of cilostazol 100 mg plus GBE 80 mg or cilostazol 100 mg plus placebo in 34 healthy Korean subjects

Parameter Cilostazol + placebo Cilostazol + GBE P value
ΔAggregation* 14.9 ± 13.9 19.5 ± 16.0 0.20
Bleeding time prolongation factor† 1.1 ± 0.6 1.2 ± 0.6 0.28
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*

ΔAggregation was calculated as follows: ΔAggregation (%) = ([A0 – At]/A0) × 100, where A0 is the average of the aggregation value at 6 and 7 h on day −1 (at the same time on day −1 as 6 and 7 h after administration on day 7) and At is the average of the aggregation value at 6 and 7 h after administration on day 7).

†

Bleeding time prolongation factor = BTt/BT0, where BT0 is the bleeding time before administration (at the same time on day −1 as 6 h after administration) and BTt is the bleeding time at 6 h after administration on day 7.

The bleeding time was not significantly different before and after treatment, nor between cilostazol plus placebo and cilostazol plus GBE (Figure 3B). The bleeding time prolongation factor was not significantly different between the two treatments (P = 0.28; Table 2).

Safety

Adverse drug reactions occurred in 26 of the 37 subjects administered the drug (n = 21 after administration of cilostazol plus placebo and n = 21 after administration of cilostazol plus GBE; Table 3). There was no significant difference in the number of subjects with adverse drug reaction between the two treatments (P = 0.89). Vascular headache, a well-known adverse reaction to cilostazol, occurred in all 26 subjects who had an adverse drug reaction. Dizziness occurred along with vascular headache in one subject following treatment with cilostazol plus placebo, and palpitations (n = 2), dizziness (n = 1) and diarrhoea (n = 1) along with vascular headache in two subjects following treatment with cilostazol plus GBE, (Table 4). These were assessed to be expected adverse drug reactions associated with cilostazol. All reactions were classified as mild to moderate and resolved completely without sequelae.

Table 3.

The total number of subjects with adverse drug reactions in the treatment groups administration of cilostazol 100 mg plus GBE 80 mg or cilostazol 100 mg plus placebo

Adverse drug reactions Total Cilostazol + placebo Cilostazol + GBE P value
Number of subjects 26/37 21/35 21/36 0.89
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Table 4.

Adverse drug reactions occurring after administration of cilostazol 100 mg plus GBE 80 mg or cilostazol 100 mg plus placebo

Adverse drug reactions Cilostazol + placebo Cilostazol + GBE
Mild Moderate Mild Moderate
Vascular headache 20 1 20 1
Diarrhoea 0 0 1 0
Palpitations 0 0 2 0
Dizziness 1 0 1 0
Total 21 1 24 1
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Discussion

This study evaluated the effect of GBE on the pharmacokinetics and pharmacodynamics of cilostazol and its two active metabolites, 3,4-dehydrocilostazol and 4′-trans-hydroxycilostazol, during 7 days of multiple dosing with cilostazol (100 mg) plus GBE (80 mg) in healthy Korean subjects. It provides evidence for no drug–herb interaction in humans between the commonly co-prescribed cilostazol and GBE. There was no significant difference in any pharmacokinetic parameter, including Css,max or AUCτ, between treatments with cilostazol plus GBE and cilostazol plus placebo. The ADP-induced platelet aggregation and bleeding time did not differ significantly between the two treatments. Moreover, no clinically significant difference was observed in the occurrence of adverse drug reactions between the two treatments.

Recently, it was reported that three of 18 commercially available GBE products were adulterated [28]. In order to ensure the quality of Ginexin® (the GBE used in this study) prior to the clinical trial, we independently compared Ginexin® and EGb 761 (standardized GBE) using a chromatographic and spectral fingerprinting method. No significant differences were observed (data not shown); therefore, the GBE used in the study was assessed to be unadulterated.

Among several studies on GBE, there have been mixed findings regarding its effects on drug metabolism and whether GBE induces or inhibits metabolic enzymes. Some studies have reported that GBE induced expression of CYPs, including CYP3A in human and rat hepatocytes [20,21], and significantly decreased concentrations of midazolam, a CYP3A probe drug [29] and omeprazole, a CYP2C19 probe drug [30]. On the contrary, other studies have reported that GBE inhibited drug-metabolizing enzymes, including CYP2C19 and CYP3A4 in vitro [31], and found that plasma concentrations of CYP3A substrates, such as midazolam and nifedipine, were significantly increased by GBE intake [32,33]. In the present study, we have tried to explore the effects of GBE on pharmacokinetics of cilostazol at steady state. Ginkgo biloba extract was not found to affect any pharmacokinetic parameters of cilostazol and its active metabolites mainly metabolized by CYP2C19 and CYP3A [22]. This result seems to be in accord with the finding of Gurley et al. that administration of GBE for 28 days did not result in a significant effect on the metabolic index of CYP3A4, CYP1A2, CYP2E1 or CYP2D6 for probe drugs in healthy adult subjects [34]. In this study, we tried to evaluate the drug interaction at the frequently co-administered dose of cilostazol and GBE. Therefore, the maximal dose of GBE and cilostazol for the treatment of peripheral arterial occlusive disease was selected. This study found no pharmacokinetic interaction between GBE and cilostazol at these doses. However, higher doses of GBE may need to be evaluated because of possible dose-dependent interaction of pharmacokinetics.

In the present study, the percentage change in ADP-induced platelet aggregation tended to be higher, without statistical significance, after co-administration of cilostazol plus GBE compared with co-administration of cilostazol plus placebo, while the change in bleeding time was similar between the two treatments. Although co-administration of GBE did not produce a statistically significant decrease of platelet aggregation compared with cilostazol alone, this result was still concordant with the finding of Ryu et al. that GBE enhanced the antiplatelet and antithrombotic effects of cilostazol without prolonging the bleeding time or causing any major safety issues [35]. There might be a possibility of an additive antiplatelet effect of GBE, because GBE has antiplatelet effects by increasing the concentration of endothelium-derived thrombolytics and inhibiting platelet activating factor [10]. The post hoc power calculation based on ΔAggregation data of Table 2 revealed a power of 0.237 for cilostazol + placebo vs. cilostazol + GBE. A sample size to evaluate pharmacokinetic parameters, which were the primary end-point, may not be enough to detect a change of platelet aggregation with larger variation.

In addition, multiple dosing for longer than 2–3 weeks might be needed in order to observe a significant effect of GBE on platelet aggregation [36]; therefore, a long-term study in a larger patient population may be needed to evaluate whether GBE has clinically important pharmacodynamic interactions with cilostazol.

The most frequently observed adverse drug reaction in the present study was vascular headache. Co-administration of cilostazol and GBE showed an adverse event frequency of 58.82%; the frequency for cilostazol plus placebo was 61.76%. This suggests that the prevalence of vascular headache did not change significantly when GBE was co-administered. Previous reports have documented that the prevalence of vascular headache with cilostazol administration is higher in healthy subjects (75%) than that in patients (33.4%) [6,37]. Thus, the high incidence rate of vascular headache in this study is not unexpected.

In conclusion, the present findings suggest that GBE has no statistically significant effects on the pharmacokinetics of cilostazol and its active metabolites in this small-scale clinical trial in healthy subjects. A large cohort study with long-term follow-up may be required to evaluate the possible pharmacodynamic interaction between cilostazol and GBE, because there was a remarkable, but not statistically significant, increase of inhibition of platelet aggregation.

Competing Interests

All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: support from SK Chemicals Co., Ltd, Korea for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work.

This study was funded by SK Chemicals Co., Ltd, Republic of Korea.

References

  • 1.Dawson DL, Cutler BS, Meissner MH, Strandness DE., Jr Cilostazol has beneficial effects in treatment of intermittent claudication: results from a multicenter, randomized, prospective, double-blind trial. Circulation. 1998;98:678–686. doi: 10.1161/01.cir.98.7.678. [DOI] [PubMed] [Google Scholar]
  • 2.Douglas JS, Jr, Holmes DR, Jr, Kereiakes DJ, Grines CL, Block E, Ghazzal ZM, Morris DC, Liberman H, Parker K, Jurkovitz C, Murrah N, Foster J, Hyde P, Mancini GB, Weintraub WS. Coronary stent restenosis in patients treated with cilostazol. Circulation. 2005;112:2826–2832. doi: 10.1161/CIRCULATIONAHA.104.530097. [DOI] [PubMed] [Google Scholar]
  • 3.Matsumoto M. Cilostazol in secondary prevention of stroke: impact of the Cilostazol Stroke Prevention Study. Atheroscler Suppl. 2005;6:33–40. doi: 10.1016/j.atherosclerosissup.2005.09.003. [DOI] [PubMed] [Google Scholar]
  • 4.Schror K. The pharmacology of cilostazol. Diabetes Obes Metab. 2002;4(Suppl. 2):S14–19. doi: 10.1046/j.1463-1326.2002.0040s2s14.x. [DOI] [PubMed] [Google Scholar]
  • 5.Kimura Y, Tani T, Kanbe T, Watanabe K. Effect of cilostazol on platelet aggregation and experimental thrombosis. Arzneimittelforschung. 1985;35:1144–1149. [PubMed] [Google Scholar]
  • 6.Yu KS, Cho JY, Jang IJ, Hong KS, Chung JY, Kim JR, Lim HS, Oh DS, Yi SY, Liu KH, Shin JG, Shin SG. Effect of the CYP3A5 genotype on the pharmacokinetics of intravenous midazolam during inhibited and induced metabolic states. Clin Pharmacol Ther. 2004;76:104–112. doi: 10.1016/j.clpt.2004.03.009. [DOI] [PubMed] [Google Scholar]
  • 7.Tamai Y, Takami H, Nakahata R, Ono F, Munakata A. Comparison of the effects of acetylsalicylic acid, ticlopidine and cilostazol on primary hemostasis using a quantitative bleeding time test apparatus. Haemostasis. 1999;29:269–276. doi: 10.1159/000022512. [DOI] [PubMed] [Google Scholar]
  • 8.Lee SW, Park SW, Kim YH, Yun SC, Park DW, Lee CW, Hong MK, Kim HS, Ko JK, Park JH, Lee JH, Choi SW, Seong IW, Cho YH, Lee NH, Kim JH, Chun KJ, Park SJ. Drug-eluting stenting followed by cilostazol treatment reduces late restenosis in patients with diabetes mellitus the DECLARE-DIABETES Trial (A randomized comparison of triple antiplatelet therapy with dual antiplatelet therapy after drug-eluting stent implantation in diabetic patients) J Am Coll Cardiol. 2008;51:1181–1187. doi: 10.1016/j.jacc.2007.11.049. [DOI] [PubMed] [Google Scholar]
  • 9.Chen KY, Rha SW, Li YJ, Poddar KL, Jin Z, Minami Y, Wang L, Kim EJ, Park CG, Seo HS, Oh DJ, Jeong MH, Ahn YK, Hong TJ, Kim YJ, Hur SH, Seong IW, Chae JK, Cho MC, Bae JH, Choi DH, Jang YS, Chae IH, Kim CJ, Yoon JH, Chung WS, Seung KB, Park SJ. Triple versus dual antiplatelet therapy in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Circulation. 2009;119:3207–3214. doi: 10.1161/CIRCULATIONAHA.108.822791. [DOI] [PubMed] [Google Scholar]
  • 10.Diamond BJ, Shiflett SC, Feiwel N, Matheis RJ, Noskin O, Richards JA, Schoenberger NE. Ginkgo biloba extract: mechanisms and clinical indications. Arch Phys Med Rehabil. 2000;81:668–678. doi: 10.1016/s0003-9993(00)90052-2. [DOI] [PubMed] [Google Scholar]
  • 11.World Health Organization. WHO Monographs on Selected Medicinal Plants: Folium. Geneva: WHO; 1999. Ginkgo. [Google Scholar]
  • 12.Klepser TB, Klepser ME. Unsafe and potentially safe herbal therapies. Am J Health Syst Pharm. 1999;56:125–138. doi: 10.1093/ajhp/56.2.125. quiz 39-41. [DOI] [PubMed] [Google Scholar]
  • 13.KFDA. Release of information: Ginexin F 80mg. Available at http://ezdrug.mfds.go.kr/kfda2 (last accessed 9 May 2013)
  • 14.Izzo AA, Ernst E. Interactions between herbal medicines and prescribed drugs: a systematic review. Drugs. 2001;61:2163–2175. doi: 10.2165/00003495-200161150-00002. [DOI] [PubMed] [Google Scholar]
  • 15.Hilton MP, Zimmermann EF, Hunt WT. Ginkgo biloba for tinnitus. Cochrane Database Syst Rev. 2013;(3) doi: 10.1002/14651858.CD003852.pub3. CD003852. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Vellas B, Coley N, Ousset PJ, Berrut G, Dartigues JF, Dubois B, Grandjean H, Pasquier F, Piette F, Robert P, Touchon J, Garnier P, Mathiex-Fortunet H, Andrieu S. Long-term use of standardised Ginkgo biloba extract for the prevention of Alzheimer's disease (GuidAge): a randomised placebo-controlled trial. Lancet Neurol. 2012;11:851–859. doi: 10.1016/S1474-4422(12)70206-5. [DOI] [PubMed] [Google Scholar]
  • 17.Gardner CD, Taylor-Piliae RE, Kiazand A, Nicholus J, Rigby AJ, Farquhar JW. Effect of Ginkgo biloba (EGb 761) on treadmill walking time among adults with peripheral artery disease: a randomized clinical trial. J Cardiopulm Rehabil Prev. 2008;28:258–265. doi: 10.1097/01.HCR.0000327184.51992.b8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Chan A, Leung H, Wu J, Chien T. Risk of hemorrhage associated with co-prescriptions for Ginkgo biloba and antiplatelet or anticoagulant drugs. J Altern Complement Med. 2011;17:513–517. doi: 10.1089/acm.2010.0295. [DOI] [PubMed] [Google Scholar]
  • 19.Choi K, Koh M. Analysis of prescribing patterns of oral anti-thrombotics in outpatients – focusing on prescriptions containing multiple drugs. JKAMCP. 2010;2:21–29. [Google Scholar]
  • 20.Deng Y, Bi HC, Zhao LZ, Wang XD, Chen J, Ou ZM, Ding L, Xu LJ, Guan S, Chen X, Zhou SF, Huang M. Induction of cytochrome P450 3A by the Ginkgo biloba extract and bilobalides in human and rat primary hepatocytes. Drug Metab Lett. 2008;2:60–66. doi: 10.2174/187231208783478489. [DOI] [PubMed] [Google Scholar]
  • 21.Umegaki K, Taki Y, Endoh K, Taku K, Tanabe H, Shinozuka K, Sugiyama T. Bilobalide in Ginkgo biloba extract is a major substance inducing hepatic CYPs. J Pharm Pharmacol. 2007;59:871–877. doi: 10.1211/jpp.59.6.0014. [DOI] [PubMed] [Google Scholar]
  • 22.Hiratsuka M, Hinai Y, Sasaki T, Konno Y, Imagawa K, Ishikawa M, Mizugaki M. Characterization of human cytochrome p450 enzymes involved in the metabolism of cilostazol. Drug Metab Dispos. 2007;35:1730–1732. doi: 10.1124/dmd.107.016758. [DOI] [PubMed] [Google Scholar]
  • 23.German Commission E. Liste der Monographien der E-Kommission (Phyto-Therapie). Available at http://buecher.heilpflanzen-welt.de/BGA-Kommission-E-Monographien (last accessed 11 May 2013)
  • 24.Bramer SL, Forbes WP. Relative bioavailability and effects of a high fat meal on single dose cilostazol pharmacokinetics. Clin Pharmacokinet. 1999;37(Suppl. 2):13–23. doi: 10.2165/00003088-199937002-00002. [DOI] [PubMed] [Google Scholar]
  • 25.Kim KA, Park PW, Hong SJ, Park JY. The effect of CYP2C19 polymorphism on the pharmacokinetics and pharmacodynamics of clopidogrel: a possible mechanism for clopidogrel resistance. Clin Pharmacol Ther. 2008;84:236–242. doi: 10.1038/clpt.2008.20. [DOI] [PubMed] [Google Scholar]
  • 26.Loscalzo J, Shafer AI. Thrombosis and Hemorrhage. 3rd edn. Philadelphia, PA: Lippincott Williams & Wilkins; 2002. [Google Scholar]
  • 27.Bramer SL, Brisson J, Corey AE, Mallikaarjun S. Effect of multiple cilostazol doses on single dose lovastatin pharmacokinetics in healthy volunteers. Clin Pharmacokinet. 1999;37(Suppl. 2):69–77. doi: 10.2165/00003088-199937002-00008. [DOI] [PubMed] [Google Scholar]
  • 28.Harnly JM, Luthria D, Chen P. Detection of adulterated Ginkgo biloba supplements using chromatographic and spectral fingerprints. J AOAC Int. 2012;95:1579–1587. doi: 10.5740/jaoacint.12-096. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Robertson SM, Davey RT, Voell J, Formentini E, Alfaro RM, Penzak SR. Effect of Ginkgo biloba extract on lopinavir, midazolam and fexofenadine pharmacokinetics in healthy subjects. Curr Med Res Opin. 2008;24:591–599. doi: 10.1185/030079908x260871. [DOI] [PubMed] [Google Scholar]
  • 30.Yin OQ, Tomlinson B, Waye MM, Chow AH, Chow MS. Pharmacogenetics and herb-drug interactions: experience with Ginkgo biloba and omeprazole. Pharmacogenetics. 2004;14:841–850. doi: 10.1097/00008571-200412000-00007. [DOI] [PubMed] [Google Scholar]
  • 31.Zou L, Harkey MR, Henderson GL. Effects of herbal components on cDNA-expressed cytochrome P450 enzyme catalytic activity. Life Sci. 2002;71:1579–1589. doi: 10.1016/s0024-3205(02)01913-6. [DOI] [PubMed] [Google Scholar]
  • 32.Uchida S, Yamada H, Li XD, Maruyama S, Ohmori Y, Oki T, Watanabe H, Umegaki K, Ohashi K, Yamada S. Effects of Ginkgo biloba extract on pharmacokinetics and pharmacodynamics of tolbutamide and midazolam in healthy volunteers. J Clin Pharmacol. 2006;46:1290–1298. doi: 10.1177/0091270006292628. [DOI] [PubMed] [Google Scholar]
  • 33.Smith MLK, Zheng YP. An open trial of nifedipine-herb interactions: nifedipine with St. John's wort, ginseng, or Gingko biloba. Clin Pharmacol Ther. 2001;69:86. [Google Scholar]
  • 34.Gurley BJ, Gardner SF, Hubbard MA, Williams DK, Gentry WB, Cui Y, Ang CY. Cytochrome P450 phenotypic ratios for predicting herb-drug interactions in humans. Clin Pharmacol Ther. 2002;72:276–287. doi: 10.1067/mcp.2002.126913. [DOI] [PubMed] [Google Scholar]
  • 35.Ryu KH, Han HY, Lee SY, Jeon SD, Im GJ, Lee BY, Kim K, Lim KM, Chung JH. Ginkgo biloba extract enhances antiplatelet and antithrombotic effects of cilostazol without prolongation of bleeding time. Thromb Res. 2009;124:328–334. doi: 10.1016/j.thromres.2009.02.010. [DOI] [PubMed] [Google Scholar]
  • 36.Braquet P. The Ginkgolides; potent platelet activating antagonists isolated from Ginkgo biloba L; chemistry, pharmacology and clinical applications. Drugs Future. 1987;12:643–688. [Google Scholar]
  • 37.Pratt CM. Analysis of the cilostazol safety database. Am J Cardiol. 2001;87:28D–33D. doi: 10.1016/s0002-9149(01)01719-2. [DOI] [PubMed] [Google Scholar]

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