Eur J Clin Pharmacol (2001) 56: 799±803
DOI 10.1007/s002280000229
PHARMACOKINETICS AND DISPOSITION
S. Kanazawa á T. Ohkubo á K. Sugawara
The effects of grapefruit juice on the pharmacokinetics
of erythromycin
Received: 25 September 2000 / Accepted in revised form: 27 September 2000 / Published online: 8 December 2000
Ó Springer-Verlag 2000
Abstract Objective: To study the e€ects of grapefruit
juice on the pharmacokinetics of erythromycin.
Methods: The e€ects of grapefruit juice intake on the
pharmacokinetics of erythromycin were investigated in
six healthy male volunteers, who received 400 mg ery-
thromycin with either water or grapefruit juice. The
measurement of erythromycin in plasma samples were
achieved by simple Sep-Pak CN cartridge extraction
coupled with the electrochemical determination HPLC
method, which was developed for the determination of
erythromycin in human plasma in the present study.
Results: Grapefruit juice, compared with water intake,
signi®cantly (P<0.05) increased the mean Cmax value
(1.65‹0.94 versus 2.51‹0.68 lg/ml) and the mean
AUC0±12 value of erythromycin (5.92‹3.25 versus
8.80‹1.32lg á h/ml). However, the Tmax and t1/2 values
of erythromycin were not a€ected by grapefruit juice
intake.
Conclusion: These results indicate that the bioavailability
of erythromycin was increased by the inhibitory e€ect of
grapefruit juice on cytochrome P450 (CYP) 3A4-medi-
ated metabolism in the small intestine.
Key words Erythromycin á Grapefruit juice á
Cytochrome P450 3A4
Introduction
A signi®cant increase in oral bioavailability by the
e€ects of grapefruit juice on CYP3A substrate drugs has
been reported in previous papers including cyclosporin
S. Kanazawa á T. Ohkubo (&) á K. Sugawara
Department of Pharmacy, Hirosaki University Hospital,
Hirosaki, 036-8563, Japan
e-mail: ok1231@mail.cc.hirosaki-u.ac.jp
T. Ohkubo
Department of Pharmacy, Hirosaki University Hospital,
Hirosaki, 036-8563, Japan
[1], terfenadine [2], felodipine [3, 4], triazolam [5] and
midazolam [6]. However, CYP3A-mediated drug inter-
action with grapefruit juice did not prolong the elimi-
nation half-life of these drugs, which increased the peak
plasma concentration (Cmax) and AUC pharmacokinetic
parameters. The mechanism of these drug-grapefruit
juice interactions has been attributed to the inhibi-
tion of ®rst-pass metabolism on CYP3A in the small
intestine [7].
On the other hand, the macrolide antibiotic erythro-
mycin, which has been widely used in clinical practice,
has been established as a potent inhibitor of CYP3A [8,
9, 10]. The inhibition mechanism of CYP3A activity by
macrolide antibiotics has been attributed to the inacti-
vation resulting from the formation of an inactive
cytochrome P450-drug complex [11]. A number of
CYP3A-mediated drug interactions with erythromycin
have been reported in previous papers [12, 13, 14, 15, 16,
17]. The elimination half-life of CYP3A-metabolized
drugs was prolonged when co-administered with ery-
thromycin because of its inhibition of CYP3A activity in
the liver. Erythromycin can increase both the Cmax and
elimination half-life in drug-drug interactions with
triazolam and midazolam [13, 16]. However, as we
described in a previous paper, the drug interaction of
alprazolam with erythromycin increased only the elimi-
nation half-life but not the Cmax [17]. It has not yet been
reported, however, how erythromycin inhibits CYP3A
in the small intestine, and how the activity of erythro-
mycin metabolism is a€ected by CYP3A in the small
intestine. The metabolic e€ect or inhibitory activity of
erythromycin on CYP3A needs to be clari®ed, because
the small-intestinal CYP enzyme has been recognized as
an important factor in the pharmacokinetics of drug
bioavailability and drug-drug interaction [18]. Previous
studies have suggested that grapefruit juice is a speci®c
inhibitor of CYP3A in the small intestine [7]. Therefore,
in the present study, we examined the drug interaction
between erythromycin and grapefruit juice using the
simple Sep-Pak CN cartridge extraction ECD-HPLC
method we have developed.
800
Materials and methods
Chemicals and reagents
Erythromycin was obtained from Sigma Co. (St. Louis, MO, USA)
and erythromycin oxime (Fig. 1) was kindly donated by Roussel
Uclaf Co. (Paris, France). Sep-Pak CN cartridge was purchased
from Waters Co. (Milford, Mass., USA). All solvents used were of
HPLC grade (Wako Pure Chemical Industries, Osaka, Japan). All
other reagents and chemicals were purchased from Wako (Osaka,
Japan) and Nakarai Tesque (Kyoto, Japan).
Apparatus
The apparatus used for HPLC was a Jasco Model PU-880 chro-
matography pump (Jasco, Tokyo, Japan) equipped with a Coulo-
chem Model 5100A electrochemical detector (Environmental
Science Association, Bedford, Mass., USA). The potential of the
electrochemical detector was set at +0.70 V versus the reference
electrode because stable and/or high sensitive chromatograms and
the least interference from endogenous substances in plasma were
obtained. Test samples were introduced using a Rheodyne Model
7120 injector (Rheodyne, Cotati, Calif., USA) with an e€ective
volume of 100 ll. Erythromycin and erythromycin oxime (internal
standard) were separated on an ODS stationary phase column
(Develosil ODS-5, 150 ´ 4.6 mm I.D., Nomura Chemicals, Seto,
Japan). The mobile phase consisted of 0.1% potassium dihydro-
genphosphate (pH 5.0)-acetonitrile (70:30, v/v). The ¯ow rate of the
mobile phase was 1.0 ml/min at ambient temperature.
Preparation of sample
There have been reports of an HPLC method for the determination
of erythromycin in plasma [19, 20, 21, 22], but these HPLC
methods used a liquid-liquid extraction method which is tedious
and time-consuming. Therefore, we developed a simple and rapid
extraction method using a Sep-Pak CN cartridge and HPLC-ECD
to determine erythromycin in plasma. Erythromycin oxime (500 ng)
in methanol (10 ll) was added to the plasma sample (1.0 ml) as an
internal standard and the plasma sample was then brie¯y mixed.
The mixture was applied to a Sep-Pak CN cartridge. The cartridge
was then washed with 5 ml of water and 10 ml of 40% methanol.
Then the desired fraction was eluted with 5 ml of 80% methanol.
The eluate was evaporated to dryness in a vacuum at 60 °C. The
Fig. 1 Mean‹SD plasma concentration±time pro®le after a single
oral dose of 400 mg erythromycin with water or grapefruit juice in
six subjects. s with water, d with grapefruit juice. Asterisk
indicates signi®cant di€erence compared with water: *P<0.05
residue was dissolved in 100 ll of mobile phase and injected into
the HPLC apparatus. Low interference from plasma was obtained
by our Sep-Pak CN cartridge extraction method.
Calibration graphs and recovery experiment
Known amounts of erythromycin in the range of 0.25±10 lg/ml
were added to blank plasma samples. These samples were treated
according to the extraction procedure described above. The peak-
height ratios of erythromycin to erythromycin oxime were mea-
sured and plotted against the concentration of analyte. Calibration
graphs for erythromycin were linear in the range 0.25±10lg/ml
(r=0.999). The limit of detection for erythromycin was 0.125 lg/ml
(signal-to-noise ratio=5).
A recovery experiment was carried out using drug-free plasma
spiked with a known amount of erythromycin. These samples were
extracted by the procedure described above. Control samples were
prepared by adding a known amount of erythromycin to 1 ml of
methanol. These control samples were not extracted, but directly
evaporated to dryness at 60 °C, and the residues were reconstituted
in mobile phase. An external standard instead of an internal
standard was added to all of these samples before the samples were
evaporated to dryness. Recoveries were determined by comparison
between solid-phase extraction and no extraction as control. The
recovery of erythromycin was determined by adding the following
four concentrations to blank plasma: 0.25, 0.75, 2, and 10 lg/ml.
The recovery values of erythromycin were 97.1%±99.3%. Coe-
cients of variation for erythromycin were less than 7.8%.
Pharmacokinetic study design
The study protocol was approved by the Ethics Committee of
Hirosaki University Hospital, and each subject gave his written
consent before the study. Six healthy male subjects (mean age‹SD:
33.5‹9.7 years, mean body weight‹SD: 62.3‹5.2 kg) partici-
pated in this study. All subjects were healthy as judged by medical
history. Subjects refrained from alcohol and medications, including
over the counter drugs, throughout the study.
The study had an open crossover design after a 4-week wash-
out period. The subjects were pretreated with either 300 ml of water
or grapefruit juice (Double strand concentrated, Dole Food,
Fla., USA) 30 min before the oral administration of 400 mg
erythromycin (a 100-mg enteric-coated tablet of Irotycin; Shionogi
Pharmaceutical, Osaka, Japan).
Blood samples (10 ml) were collected by vein puncture at 0, 0.5,
1, 2, 3, 4, 6, 8, and 12 h after erythromycin administration. Plasma
samples were separated by centrifugation at 1900g for 15 min and
stored at )30 °C until analysis.
Data analysis
The area under the concentration time curve of erythromycin from
0 to 12 h (AUC0±12) was calculated by trapezoidal rules. The
elimination rate constant (Ke) of erythromycin was estimated from
the nonlinear least-squares regression analysis of the terminal log-
linear concentration-time data, and the elimination half-life (t1/2)
was calculated from 0.693/Ke. The peak plasma concentration
(Cmax) and the time reached to Cmax (Tmax) were read from the
observed plasma concentration-time data in each of the individuals.
Di€erences in pharmacokinetic parameters for erythromycin
and those after coadministration of grapefruit juice were analyzed
by the paired Student t test and P<0.05 was considered statistically
signi®cant.
Results
Mean plasma concentration-time pro®les after admin-
istration of 400 mg erythromycin with water and with
 801

grapefruit juice are shown in Fig. 1. Pharmacokinetic
parameters of erythromycin with water and with
grapefruit juice are summarized in Table 1. During the
grapefruit juice phase, the mean Cmax (1.65‹0.94 lg/ml
in water versus 2.51‹0.68 lg/ml in grapefruit juice) and
the AUC0±12 value of erythromycin (5.92‹3.25 lg á h/ml
in water versus 8.80‹1.32 lg á h/ml in grapefruit juice)
signi®cantly increased compared with water. Both the
Cmax and the AUC0±12 were more than 1.5 times higher
during the grapefruit juice phase. However, the Tmax
and t1/2 values of erythromycin were not signi®cantly
di€erent between the water and grapefruit juice phases.
Discussion
Our project was directed toward examination of the
e€ects of grapefruit juice on the pharmacokinetics of
erythromycin in healthy male subjects. Table 1 shows the
pharmacokinetic parameters obtained for erythromycin,
which was administered as a single oral 400 mg dose. The
values obtained for Tmax, Cmax, and AUC correlated
roughly with previous papers [23, 24]. The di€erence in
value of t1/2 between our results and previous results
originated from interindividual and/or ethnic di€erences.
Shimada et al. reported interindividual variation in
human liver CYP3A [25] and Sowunmi also reported
ethnic di€erence variation of nifedipine pharmacokinetics
as an indicator of CYP3A activity [26]. Furthermore, the
erythromycin was decomposed by gastric acid ¯uid after
an oral dose [27]. Therefore, the bioavailability and
pharmacokinetic parameters of erythromycin could be
a€ected by these factors, which can not be anticipated.
There was some possibility that the di€erence in
statistical signi®cance on the pharmacokinetics could
not be detected between the grapefruit juice phase
and the control phase experiment because the e€ect
of grapefruit juice was counteracted by the factors
described above. However, our present results indicate
that the Cmax and AUC0±12 were increased by grapefruit
juice treatment compared with the water phase (Table 1,
Fig. 1). The speci®c inhibition of CYP3A activity in the
small intestine by grapefruit juice has been reported in
previous papers [1, 6, 28]. Our present results indicate
that the inhibition of CYP3A by grapefruit juice in the
small intestine caused an increase in the Cmax and the
AUC0±12 of erythromycin, which means that there was a
decrease in the ®rst-pass metabolism of erythromycin in
the small intestine. Therefore, the metabolism of ery-
thromycin by CYP3A in the small intestine has been
clearly demonstrated in the present study. The t1/2 values
of erythromycin were not altered in the experimental
phase with grapefruit juice. These results support our
hypothesis because the elimination of erythromycin is
prolonged by inhibition of CYP3A in the liver. It was
considered that the low bioavailability of erythromycin
was due to high hepatic extraction and decomposition
in acidic gastric ¯uid. However, Somogyi et al. [29]
described an erythromycin systemic blood clearance of
164 ml/min and found the hepatic extraction ratio to be
0.11 and estimated bioavailability at 89%. They sug-
gested that drug metabolism plays a role in the gut wall's
ability to contribute to erythromycin's low bioavail-
ability. Another previous paper described that the total
body clearance values after intravenous administration
were 438 ml/min [30], 417 ml/min [31], and 570 ml/min
[32], respectively. In a previous study, Bailey et al. [33]
described that the Cmax, AUC, and the t1/2 of felodipine
increased with erythromycin pretreatment, whereas the
t1/2 of felodipine was not a€ected by grapefruit juice
treatment. Their study and our results both indicate that
erythromycin is metabolized by both intestinal and liver
CYP3A.
Kolars et al. described that the CYP3A4 protein was
present in the liver and jejunum, whereas CYP3A5 was
the major protein present in the stomach. Their paper
suggested that the di€erence in the relative expression of
CYP3A4 and CYP3A5 may account for speci®c organic

Table 1 Pharmacokinetic parameters of erythromycin after a single dose of 400 mg erythromycin with water or grapefruit juice in six
subjects
Subjects Cmax (lg/ml) Tmax (hr) Ke (hr±1) t1/2 (hr) AUC (0±12) (lg á hr/ml)

Water 1 1.59 4 0.27 2.57 6.20

2 1.65 4 0.40 1.72 8.93
3 1.93 4 0.42 1.66 4.48
4 0.30 4 0.28 2.52 1.11
5 1.28 3 0.15 4.52 4.72
6 3.19 4 0.26 2.67 10.07
Mean‹SD 1.65‹0.94 3.83‹0.41 0.30‹0.10 2.61‹1.04 5.92‹3.25
Grapefruit juice 1 2.84 4 0.42 1.63 10.12
2 2.62 4 0.30 2.30 9.01
3 2.38 3 0.44 1.58 7.92
4 1.93 4 0.39 1.83 6.61
5 2.65 3 0.12 5.92 9.31
6 3.29 3 0.31 2.22 9.85
Mean‹SD 2.51‹0.68** 3.50‹0.55 0.33‹0.12 2.58‹1.66 8.80‹1.32*

*P<0.05
**P<0.01 when compared with water
802
di€erences in the metabolism of many drugs [34]. In
another report [35], di€erences in the stereospeci®c
pharmacokinetics of nimodipine were described between
oral administration and intravenous routes of adminis-
tration. In our previous report, we also observed
di€erent e€ects with grapefruit juice in the pharmaco-
kinetics of nicardipine between oral and intravenous
doses [36]. It is possible that there may be a di€erence
in stereoselectivity between CYP3A of the liver and
gastrointestinal tracts, although this hypothesis has not
been proven. Also, Somogyi et al. [29] have described
the e€ects of acidic degradation of erythromycin for
pharmacokinetics. The erythromycin bioavailability was
43% when the erythromycin solution was administered
at duodenal ¯uid, and the bioavailability of orally ad-
ministered erythromycin was 32%. There was negligible
10% di€erence between duodenal and oral doses.
Somogyi et al. [29] described that the acidic degradation
of erythromycin had the least e€ect on pharmacokinetics
which depended more on the gut wall's ability than on
acidic degradation.
On the other hand, it is well known that erythromycin
is a substrate of P-glycoprotein (P-gp) [37] which has an
e€ect on the pharmacokinetics of orally administered
erythromycin mediated by the gut wall P-gp [38]. The
e€ects of grapefruit juice on the gut wall P-gp were not
suciently clari®ed.
In the present study, we have established the metab-
olism of erythromycin by CYP3A in the gastrointestinal
tract. However, in our previous paper [17], erythromycin
did not inhibit the metabolism of alprazolam in the
gastrointestinal tract because the Cmax of alprazolam
was not increased by erythromycin treatment. On the
other hand, the metabolism of triazolam in the gastro-
intestinal tract was inhibited by erythromycin treatment
[16]. However, both alprazolam and triazolam metabo-
lism in the liver were inhibited by erythromycin [16, 17].
Although the mechanism for these phenomena are not
entirely clear, we think that the contribution of CYP3A4
to erythromycin metabolism in the gastrointestinal tract
is a very important factor a€ecting the bioavailability
of drugs. Further clari®cation of the characteristics of
metabolism and/or inhibition by erythromycin will be
valuable in the future.
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