Download Effect of grapefruit juice on bioavailability of montelukast

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Effect of Grapefruit Juice on Bioavailability of Montelukast
Cemal Cingi, MD; Sema Zer Toros, MD; Melek Kezban Gürbüz, MD; Iskender Ince, MD;
Hamdi Cakli, MD; Nagehan Erdogmus, MD; Ercument Karasulu, MD; Ercan Kaya, MD
Objectives/Hypothesis: The aim of this study was to investigate possible interactions between grapefruit juice and
montelukast for up to 4 hours.
Study Design: A prospective, crossover study with 23 healthy volunteers was performed in two sessions.
Methods: In the first session, volunteers were treated with oral montelukast 10 mg once daily with 250 ml water. After
a 10-day washout period, the same volunteers were treated with 10 mg montelukast with 250 ml grapefruit juice. Blood samples were collected 2, 3, and 4 hours after drug administration and kept at 80 C after both applications. Plasma samples
were analyzed for montelukast concentration.
Results: The mean plasma concentration of montelukast across all time intervals was significantly greater (P ¼ 0.0001)
for those given grapefruit juice (517, 484, and 440) versus those treated with water (366, 356, and 292). Moreover, with
respect to the time the sample was collected, there was no significant difference (P ¼ 0.13) in the mean total plasma concentration up to 4 hours after montelukast ingestion for either group. There was a significant difference between the groups
according to the area under curve with regard to marginal and cumulative values for all different time intervals (P < 0.05).
Conclusions: Plasma concentration of montelukast was higher when administered with grapefruit juice, as compared to with
water. This may have been due to the effect of grapefruit on liver metabolism of montelukast and the cytochrome P450 system.
Key Words: Grapefruit juice, montelukast, allergy, bioavailability, asthma, drug interactions.
Level of Evidence: 2b.
Laryngoscope, 123:816–819, 2013
INTRODUCTION
It has been reported in pharmacological literature
that, when any two active ingredients are combined, the
interaction can potentially cause alterations in the molecular structure and pharmacokinetic properties of the
interacting ingredients. This type of drug–drug interaction not only affects the bioavailability of the ingredients
but also their beneficial and harmful effects. One such
example of this is the effect of grapefruit juice on the
plasma levels of various drugs. In previous studies,
grapefruit juice has been shown to augment the bioavailability of several drugs, increasing both the beneficial
and adverse effects of the medication, despite the grapefruit juice being consumed several hours beforehand.1
Previously studied drugs include triazolam, midazolam,
terfenadine, cyclosporine, and dihydropyridine calcium
channel blockers, including felodipine, nifedipine, nitrendipine, and nisoldipine.2 The bioactive chemical
compounds (furanocoumarins) present in grapefruit
degrade and inhibit intestinal cytochrome P450 (CYP3A4)
activity, which regulates drug metabolism. In fact,
CYP3A4 levels have been shown to be reduced by as
much as 47% 4 hours after grapefruit juice ingestion.3
We designed a study to investigate the effect of
grapefruit juice on the bioavailability of montelukast, a
leukotriene receptor antagonist with proven efficacy in
asthma and allergic rhinitis, metabolism of which is primarily though the CYP450 system.4 Although the
scientific literature has some published reports on the
effectiveness of montelukast in combination with antihistamines and steroids,4–6 the data regarding the drug and
food interactions for montelukast are scarce. Based on
previous studies, we hypothesized that that the plasma
level of montelukast would be higher in individuals taking
the drug with grapefruit juice, as compared to with water.
MATERIALS AND METHODS
From the Department of Otorhinolaryngology (C.C., M.K.G., H.C., N.E.,
E.K.), Osmangazi University, Medical Faculty, Eskisehir; the Department
of Otorhinolaryngology/Head and Neck Surgery (S.Z.T.), Haydarpasa
Numune Research and Education Hospital, Istanbul, Center for Drug
Research & Development and Pharmacokinetic Applications (I.I., E.K.I.I.,
_
E.K.X), Ege University, 35100 Bornova, Izmir,
Turkey.
Editor’s Note: This Manuscript was accepted for publication
August 3, 2012.
The authors have no funding, financial relationships, or conflicts
of interest to report.
Send correspondence to Sema Zer Toros, M.Saadettin Sokak, Saadet Apartmanı, No: 3 D: 4, Ortak€
oy /Besiktas, Istanbul, Turkey, PK:
34347. E-mail: [email protected]
DOI: 10.1002/lary.23700
Laryngoscope 123: April 2013
816
The study was a prospective, parallel group study conducted between April 1, 2011, and April 20, 2011, at the
Department of Ear, Nose, and Throat, University of Osmangazi,
Turkey. Approval for the study was obtained from the Ethics
Committee, and informed consent was obtained from each participant upon enrollment.
Study Population
The study group comprised 23 healthy volunteers (12 male,
11 female) aged 22 to 25 years. Patients with concomitant illness
(malignancy, hepatic, psychiatric, endocrine, or other major systemic diseases); drug users and smokers were excluded.
Cingi et al.: Effect of Grapefruit Juice on Bioavailability of Montelukast
TABLE I.
Comparisons of Plasma Montelukast Concentrations Between the Test Groups According to Time (ANOVA test results).
Time
T¼2
T¼3
T¼4
Toplam
Treatment
N
Mean
StdDev
N
Mean
StdDev
N
Mean
StdDev
N
Mean
StdDev
ANOVA Test Results
GM
22
517.34
221.83
22
484.01
221.51
23
440.18
230.36
67
479.91
223.56
F ¼ 21.19,
P ¼ 0.0001 <0.05*
M
23
365.62
194.49
22
355.79
132.86
23
292.34
105.50
68
337.65
150.63
Toplam
45
439.79
219.73
44
419.90
191.80
46
366.26
192.28
135
408.25
202.63
F ¼ 2.12,
P ¼ 0.1254 >0.05
*P < 0,05.
Study Design
This was a crossover study that was performed in two sessions (or phases), with a 10-day washout period between each
session to allow complete elimination of the study medication.
No medication was allowed during the washout period. Phase 1:
volunteers were given 10 mg montelukast orally with 250 ml
water. Blood samples were collected at 2, 3, and 4 hours after
treatment, and kept at 80 C (Group M). Phase 2: the same
volunteers were given 10 mg montelukast together with 250 ml
grapefruit juice 10 days after phase 1. Blood samples were collected at 2, 3, and 4 hours after treatment, and kept at 80 C
(Group GM). The time to reach plasma peak concentration for
montelukast is 3 to 4 hours; therefore, blood samples were not
taken after 4 hours.
in phase 2, in which montelukast was administered with
grapefruit juice.
Montelukast Concentration
The mean plasma concentration of montelukast at
all time points was significantly greater for those given
grapefruit juice (517, 484, and 440 at 2, 3, and 4 hours,
respectively) versus those treated with water (366, 356,
and 292) (F ¼ 21.19; P ¼ 0.0001, P < 0.05) (Table I).
Moreover, with respect to the time the sample was collected, there was no significant difference (P ¼ 0.13) in
the mean total plasma concentration up to 4 hours after
montelukast ingestion for either group (t ¼ 2 h, 3 h, and
4 h; F ¼ 2.12; P ¼ 0.1254 and P > 0.05).
Measurement of Serum Levels of Montelukast
All samples were stored in dry ice and transferred to Ege
University Center for Drug Research & Development and Pharmacokinetic Applications (ARGEFAR). Measurements were
performed with HPLC (API 4000 LC/MS/MS), using a Thermo
Scientific HyPURITY C18 100 2.1 mm i.d. 3 lm column.
Extraction was performed as fluid-fluid. The calibration samples have been prepared by spiking reference standard into zero
plazma at six different levels: 4.0, 10.0, 50.0, 100.0, 200.0, 500.0
ng/mL concentrations for montelukast have been constructed.
Limit of detection (LOD) and limit of quantitation (LOQ) values
were 0.017 ng/ml and 0.051 ng/ml for montelukast, respectively.
Statistical Analysis
Significant differences in the mean plasma concentration
of montelukast in the M and GM groups at 2, 3, and 4 hours
were calculated and recorded using a repeated-measures analysis of variance (ANOVA). The model included time and
application type effect. Paired comparisons between levels of
time effect (2, 3, and 4 h) were done using Bonferroni correction. Marginal and cumulative parameters were taken into
account in evaluating the area under the curve (AUC). As a
marginal parameter, only the AUC within the relevant time period was taken into account. The total AUC up to the relevant
time was taken into account as a cumulative area parameter. T
test was used in the comparison of mean values of application
types separately for each time point for statistical evaluation of
both parameters. Statistical analysis was performed using SAS
9.2; P < 0.05 was considered to be statistically significant.
RESULTS
Twenty-three healthy volunteers were administered
montelukast in phase 1 of the study and 22 participated
Laryngoscope 123: April 2013
Montelukast AUC
Marginal AUC for montelukast was significantly
greater in volunteers given grapefruit juice, as compared
to water, at three different time intervals: 0 to 2, 2 to 3,
and 3 to 4 hours (t ¼ 2.44, P ¼ 0.0188; t ¼ 2.81, P ¼
0.0074; t ¼ 2.79, P ¼ 0.0074; P < 0.05) (Tables II and
III). Cumulative AUC values differed significantly
between the groups at the three different time intervals,
0 to 2, 2 to 3, and 3 to 4 hours (t ¼ 2.44, P ¼ 0.0188; t ¼
2.64, P ¼ 0.0115; t ¼ 2.99, P ¼ 0.0047; P < 0.05). Those
given grapefruit juice had significantly higher cumulative AUC values than those given water. These results
demonstrated that the elimination rate of montelukast
decreased with grapefruit juice, resulting in higher serum levels.
DISCUSSION
Grapefruit is considered to be a healthy food
because it is associated with improved insulin resistance, decreased fasting blood glucose and insulin, serum
total cholesterol and triglyceride levels.3 It is reported to
cause significant weight loss, making it part of many
diets.7
Grapefruit juice appears to inhibit CYP3A4, an important isozyme of cytochrome P450, because it oxidizes
a broad range of drugs and xenobiotics.1 CYP3A4 is common in the lumen of the gastrointestinal tract, but it is
also found in the liver, testes, lungs, kidneys, and central nervous system.8 Flavanoids (naringin and
naringenin) and furanocoumarins (bergamottin and 6
Cingi et al.: Effect of Grapefruit Juice on Bioavailability of Montelukast
817
TABLE II.
Comparisons of Marginal AUC Values of the Test Groups According to Time Intervals.
Time
t ¼ 0–2
t ¼ 2–3
t ¼ 3–4
Treatment
N
Mean
StdDev
N
Mean
StdDev
N
Mean
StdDev
GM
22
517.34
221.83
22
500.68
197.04
23
464.59
202.13
M
23
365.62
194.49
22
362.48
119.32
23
334.72
93.90
t ¼ 2.44, P ¼ 0.0188 <0.05*
t test results
t ¼ 2.81, P ¼ 0.0074 <0.05*
t ¼ 2.79, P ¼ 0.0074 <0.05*
*P < 0,05.
TABLE III.
Comparisons of Cumulative AUC Values of the Test Groups According to Time Intervals.
Time
t ¼ 0–2
t ¼ 0–3
t ¼ 0–4
Treatment
N
Mean
StdDev
N
Mean
StdDev
N
Mean
StdDev
GM
22
517.34
221.83
22
1018.02
407.12
22
1476.50
556.31
M
t test results
23
365.62
194.49
t ¼ 2.44, P ¼ 0.0188 <0.05*
22
731.64
304.75
t ¼ 2.64, P ¼ 0.0115 <0.05*
22
1068.13
319.03
t ¼ 2.99, P ¼ 0.0047 <0.05*
*P <0,05.
0
,70 -dihydrobergamottin) are the ingredients of grapefruit juice that inhibit CYP3A4 enzyme. Inhibition of
this enzyme results in increases in AUC and Cmax levels of drugs that are metabolized by CYP3A4.1,9,10
Therefore, bioavailability of those drugs is improved after consuming grapefruit juice.2
Montelukast is one of the drugs that is metabolized
by the cytochrome P450 enzyme system, and CYP3A4
and CYP2C8 are the major P450 enzymes involved in
the turnover of montelukast.11 Montelukast blocks cysteinyl-leukotriene receptors and inhibits endogenous
mediators of inflammation in allergic airway diseases.
Initially developed as a treatment for asthma, montelukast has been increasingly accepted for many indications
such as allergic rhinitis and chronic urticaria.4,12,13
Generally, montelukast is considered to be a safe
drug. No clinically significant changes in vital signs, laboratory parameters, or ECG criteria have been reported
in studies investigating effectiveness of montelukast.
The most commonly reported treatment-related adverse
event was headache (3.5%).12,14 There are also no
reports of significant adverse reactions of montelukast
in combination with antihistamines or steroids. Nevertheless, adverse effects may be expected in the case of
grapefruit juice because it increases the serum level of
montelukast by inhibiting its metabolism with CYP3A4.
The current study was planned to investigate the
potential interaction between montelukast and grapefruit juice. To the best of our knowledge, this is the first
study to show reduced montelukast metabolism with as
little as 250 ml grapefruit juice. Our results indicated
that both marginal and cumulative AUC values were
higher in volunteers taking montelukast with grapefruit
juice, as compared to with water, at all different time
intervals. This demonstrates that grapefruit juice
increases the serum levels of orally administered
Laryngoscope 123: April 2013
818
montelukast by reducing CYP3A4-mediated metabolism
of the drug. It may be important in patients with hepatic
disorders because montelukast is metabolized in the
liver. In addition, grapefruit interacts with many drugs
and increases their bioavailability. Thus, it is necessary
to be careful in allergic patients who need to take additional drugs also known to interact with grapefruit, such
as anxiolytics, neuropsychiatrics, antiarrhythmics, calcium channel blockers, HMG-CoA reductase inhibitors,
and immunosuppressants.15
CONCLUSION
The results of this study demonstrated reduced
montelukast metabolism with grapefruit juice, and
increased drug serum levels. It may be appropriate to
advise patients taking montelukast for allergic airway
disease not to drink grapefruit juice simultaneously.
They should be notified about the possible interactions
between montelukast and grapefruit juice.
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