ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Apr. 1988, p. 561-565 Vol. 32, No.

4
0066-4804/88/040561-05$02.0O/O
Copyright C 1988, American Society for Microbiology

Pharmacokinetic Advantages of Erythromycin Estolate over

Ethylsuccinate as Determined by High-Pressure
Liquid Chromatography
DANIEL CROTEAU, MICHEL G. BERGERON, AND MARC LEBEL*
Ecole de Pharmacie, Universite' Laval, and Service d'Infectiologie, Centre Hospitalier de 1' Universite Laval,
Quebec, Quebec GJ V 4G2, Canada
Received 17 August 1987/Accepted 5 January 1988

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The pharmacokinetics of erythromycin estolate (500 mg) and erythromycin ethylsuccinate (600 mg) were
compared in 12 healthy volunteers after single doses and after repeated oral doses (every 8 h). High-pressure
liquid chromatography with electrochemical detection was used to determine concentrations in plasma and
urine of estolate, ethylsuccinate, and erythromycin base. The maximum concentration of drug in the serum, the
half-life, and the area under the curve for erythromycin estolate were significantly greater than those of
erythromycin ethylsuccinate after both regimens. After single and multiple doses, the respective areas under
the curve of erythromycin base generated by estolate formulation were 3 and 1.6 times greater (P < 0.05) than
those of ethylsuccinate. The lower percentage of hydrolysis of erythromycin estolate (41 versus 69%) combined
with its longer half-life (5.47 versus 2.72 h) and its larger area under the curve (30.61 versus 4.68 ,ig * h/ml,
after multiple doses) could explain these differences. This study underscores the need for a specific
high-pressure liquid chromatography assay and the importance of wide variability, rate-limited processes,
changes with multiple doses, and the appearance of a second peak when one studies the pharmacokinetics of
erythromycin esters. The pharmacokinetic data presented in this study reinforce the clinical advantages of
erythromycin estolate over erythromycin ethylsuccinate.

Recent clinical trials suggest that erythromycin estolate is
more effective than erythromycin ethylsuccinate in the treat-
ment of streptococcal pharyngitis (13, 15), even at a lower
dosage (16). To be active, the esters of erythromycin need to
be hydrolyzed to erythromycin base (35). Higher concentra-
tions in plasma of erythromycin base resulting from a
purported better absorption of erythromycin estolate has
often been evoked to explain these differences (11, 14, 28).
Higher levels of erythromycin estolate in plasma have also
been suggested to be artifacts of the bioassay itself (28).
Thus, resolution of this controversy has been delayed by the
lack of a specific assay that can provide valuable pharmaco-
kinetic data on erythromycin estolate, ethylsuccinate, and
their respective erythromycin bases (14). The purpose of this
study was to compare concentrations in plasma of erythro-
mycin estolate (500 mg), erythromycin ethylsuccinate (600
mg), and their respective bases in healthy adult volunteers
after administration of single and multiple doses by using a
high-pressure liquid chromatography assay with electro-
chemical detection.
MATERIALS AND METHODS
Subjects and study design. Twelve healthy volunteers
(three women and nine men) between 18 and 39 years old
(mean age, 23.8 ± 6.9 years) gave their written informed
consent to participate in the study. The protocol was ap-
proved by the Centre Hospitalier de l'Universitd Laval
Human Research Review and Pharmacology-Therapeutics
Committees. The mean weight of the subjects was 69.2 ± 9.8
kg (range, 53.5 to 87.0 kg). All subjects were judged to be
healthy on the basis of history, physical examination, chem-
istry profile, complete blood count, and urinalysis. None had
a history of hepatic, renal, or neoplastic disease or known
*
Corresponding author.
561
previous allergy to macrolide compounds. No medication
was allowed at the time of study, and alcoholic beverages
were withheld 24 h before and during the study. Volunteers
had to refrain from any strenuous or athletic activity during
the study period but were allowed to circulate around the
pharmacokinetic research unit.
On the morning of day 1 after an overnight fast (nothing by
mouth) each subject received orally, in a randomized cross-
over study, a single dose of erythromycin estolate (Ilosone,
500 mg of base equivalent; Eli Lilly Canada Inc., Toronto) or
erythromycin ethylsuccinate (600 mg of base equivalent;
Laboratoires Abbott Limitde, Montreal) taken with 150 ml of
drinking water. Starting on the morning of day 5 and
continuing through day 7, each volunteer was instructed to
take (in an outpatient environment) nine consecutive doses
(every 8 h) of the same drug as on day 1 in a fasting state. A
1-h fast before or a 2-h fast after drug administration was
dictated during this multiple-dosage regimen. A final dose
was given on the morning of day 8 with at least 150 ml of
drinking water after an overnight fast. Each subject was
studied on four separate occasions.
Each subject was issued more tablets than required by a
single-blinded procedure. Compliance was verified by count-
ing unused tablets at the end of treatment.
Plasma and urine sampling. Blood samples were drawn
from an intravenous catheter in an antecubital vein at 0,
0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, and 12 h
after a single dose. After the last dose, additional blood was
drawn at 24 h. A dilute heparin solution (33 U/ml) was used
to maintain patency of the catheter, and at least 1.5 ml of
blood was removed and discarded before drawing blood.
Samples (10 ml) were collected into chilled VACUTAI-
NERs (Becton Dickinson Vacutainer Systems, Rutherford,
N.J.) containing EDTA as an anticoagulant. The blood
sample was immediately placed into an ice bath until it was
562 CROTEAU ET AL. ANTIMICROB. AGENTS CHEMOTHER.

10 -

E
o.yo.o.-o
z
0
c- 1-

0 z
z w
w 0
0 z
z 0
0 0

0 1 2 3 4 5 6 7 8 9 10 11 12
0 1 2 3 4 5 6 7 8 9 10 11 12
TIME (HOURS)

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TIME (HOURS)
FIG. 1. Concentrations in plasma of erythromycin estolate (500-
mg dose) (0) and erythromycin base (0) after a single dose in one
typical volunteer.
FIG. 3. Concentrations in plasma of erythromycin estolate (500-
mg dose) (@) and erythromycin base (0) after multiple doses (every
8 h) in one typical volunteer.

spun in a refrigerated centrifuge (900 x g, 10 min). The
collected plasma was then frozen at -20°C until assayed.
Urine was collected immediately before dose 1 and then at
intervals between 0 and 2, 2 and 4, 4 and 8, and 8 and 12 h
after dose 1 and 12 and 24 h after dose 10.
Sample analysis. Plasma and urine samples were analyzed
for erythromycin base and erythromycin estolate or eryth-
romycin ethylsuccinate by a reversed-phase high-pressure
liquid chromatography procedure with electrochemical de-
tection developed in our laboratory (12). Briefly, separation
of erythromycin base, roxithromycin (internal standard),
and erythromycin estolate or erythromycin ethylsuccinate
was achieved by using electrochemical detection at +0.9 V
(against Ag-AgCl) and a NovaPak C18 column (Waters
Scientific, Mississauga, Ontario, Canada). The mobile phase
consisted of 56% sodium acetate buffer (56 mM-40%
acetonitrile-4% methanol, adjusted to pH 7.0 and pumped at
1.1 ml/min. Retention times were 6.0, 14.7, 34.7, and 35.4
min, respectively, for erythromycin base, roxithromycin,
erythromycin estolate, and erythromycin ethylsuccinate.
Plasma sample preparation involved extraction with ether
(plasma-ether, 1:2.5, vol/vol), evaporation to dryness, re-
constitution with acetonitrile (100 ,ul) to concentrate the
sample, and injection of 40 ,ul onto the column.
The sensitivity of the assay has been evaluated to 0.25
jxg/ml (10 ng). The coefficient of variation from day to day
was 3.2 to 10.3%, and recoveries from plasma were 55, 68,
77, and 74%, respectively, for erythromycin base, roxi-
thromycin, erythromycin estolate, and erythromycin ethyl-
succinate. Linear regression analysis of the standard calibra-
tion lines in plasma yielded correlations of 0.982, 0.990, and
0.987 for erythromycin base (0 to 10 p.g/ml), erythromycin
estolate (0 to 10 ,ug/ml), and erythromycin ethylsuccinate (0
to 3 ,ug/ml), respectively.
Pharmacokinetic analysis. Because of the appearance of a
second peak in the curves of level in plasma versus time,
noncompartmental pharmacokinetic analysis was used (Fig.
1 through 4). The absorption constant (Ka) was obtained
from Pharm I by using the method of residuals (25). The
elimination constant (kel) was derived from linear regression
of the terminal log-linear portion of individual plots of
concentration in plasma versus time.
The area under the curve of concentration in plasma
versus time (AUC) from time zero to infinity (AUC,OO) was
calculated with conventional linear trapezoidal and extrap-
olation methods. The apparent total clearance (CL/F) of
erythromycin base or erythromycin esters was estimated
from the following model-independent pharmacokinetic
equations: CL/F = dose/AUC., for a single dose and CL/F
= dose/AUCO_8 h after the last dose (where 8 h is the
interval). To simplify comparisons, the same dose (500 or
600 mg) was used for erythromycin base and erythromycin

E
E
CD
z
0 z
I-
1- 0
c-
z
w z
0 w
z
0 z
0) 0
0

2 3 4 5 6 7 8 9 10 11 12
1
TIME (HOURS) TIME (HOURS)
FIG. 2. Concentrations in plasma of erythromycin ethylsucci- FIG. 4. Plasma concentrations of erythromycin ethylsuccinate
nate (600-mg dose) (0) and erythromycin base (0) after a single dose (600-mg dose) (0) and erythromycin base (0) after multiple doses
in one typical volunteer. (every 8 h) in one typical volunteer.
VOL. 32, 1988 ADVANTAGE OF ERYTHROMYCIN ESTOLATE OVER ETHYLSUCCINATE 563

esters in the calculation of CL/F. Renal clearance (CLR) was
calculated by using the following relationship: CLR= Ae (t1
- t2)/AUC (t1 - t2), where Ae is the amount of erythromycin
base, erythromycin estolate, or erythromycin ethylsuccinate
eliminated unchanged in urine from time t1 to t2. The
apparent nonrenal clearance (CLNR/F) was estimated by
subtracting CLR from CL/F. Note that CLNR/F of the esters
involves both elimination from the body and hydrolysis to
erythromycin base. The apparent volume of distribution at
steady state (V1r5/F) after a single dose was calculated from
the following relationship: V551F = (dose AUMC/AUC2) -
(dose/KaAUC) (31), where AUMC is the area under the first
moment of the concentration-time curve. After the last dose,
V,,/F was determined by the following equation: V,j/F =
(dose AUMC/AUC2) - (dose/KaAUC), where AUC is equal
after dose 10, erythromycin estolate was still detectable in
four volunteers compared with only one volunteer with the
ethylsuccinate form.
The pharmacokinetic parameters estimated from plasma
concentration data for erythromycin estolate and erythromy-
cin ethylsuccinate are listed in Table 1. The mean absorption
rate constant (Ka) of erythromycin ethylsuccinate after mul-
tiple doses was greater than that of erythromycin estolate
(3.96 versus 1.40 per h; P < 0.01). Erythromycin estolate
was eliminated more slowly than erythromycin ethylsucci-
nate (half-life, 3.04 versus 1.12 h after a single dose and 5.47
versus 2.72 h after multiple doses; P < 0.05); moreover,
respective half-lives in plasma increased after the last dose
(P < 0.05). Erythromycin ethylsuccinate showed a larger
VSs/F than estolate after single (8.94 versus 1.84 liters per kg;

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to AUCSS(>t) and AUMC = AUMCSS(O,) - [AUCSs(O)/Ka
+ TAUCSS( =)I (34).
Statistical analysis. Analysis of variance for repeated mea-
sures was used to determine the statistical significance of
plasma pharmokinetic parameters. The Wailer-Duncan test
was used to compare the means (32). A P of <0.05 was
considered statistically significant.
RESULTS
Levels of erythromycin base and erythromycin estolate or
erythromycin ethylsuccinate in plasma from four typical
volunteers are presented in Fig. 1 to 4. Individual patients
evidenced concentration curves in plasma with humps that
were no longer identifiable in the mean-value curves ob-
tained by combining the individual curve and superposing
the different points of fluctuation.
Erythromycin esters. After the first dose, the peak concen-
tration in plasma (Cm.,) of erythromycin estolate was 3.08 +
1.14 ,ug/ml (mean + standard deviation), compared with 0.91
± 0.69 pug/ml for erythromycin ethylsuccinate, and occurred
about 1 h later than the peak for erythromycin ethylsuccinate
(2.65 ±1.23 versus 1.27 0.49 h). Eight hours after
± 1.6 times greater (14.56 versus 9.02 ug h/ml; P < 0.05) than
P < 0.01) and multiple doses (7.76 versus 2.11 liters per kg;
P < 0.01).
The AUC for erythromycin estolate was much greater
than that for erythromycin ethylsuccinate after both a single
dose (AUCOC, 20.39 versus 1.88 ,ug. h/ml; P < 0.01) and
multiple doses (AUCOJ8 h, 30.61 versus 4.68 ug * h/ml; P <
0.01). In fact, erythromycin ethylsuccinate was cleared from
the body 8 to 15 times more rapidly than erythromycin
estolate as shown by their CL/Fs after both a single dose
(7,502 versus 572 ml/min) and multiple doses (2,415 versus
314 ml/min). Multiple dose administration did not seem to
affect significantly CLR of erythromycin estolate but greatly
reduced that of erythromycin ethylsuccinate after the last
dose from 42.3 to 22.4 ml/min (P < 0.01).
Erythromycin base. The pharmacokinetic parameter esti-
mated data for erythromycin base are listed in Table 2. After
a single dose there was no significant difference between the
Cmax, Tmax, and volume of distribution of erythromycin base
generated from erythromycin estolate or ethylsuccinate (P >
0.05). In contrast, CL/F and CLR were significantly different
(P < 0.01).
The AUC of erythromycin base derived from estolate was
-

administration of a single dose, erythromycin ethylsuccinate
was undetectable in plasma in all 12 volunteers, whereas
erythromycin estolate was still present after 12 h in all
volunteers. After dose 10, the erythromycin estolate peak
concentration was higher than it was after a single dose, as
anticipated from pharmacokinetic theory (P < 0.01). At 24 h
that of base derived from erythromycin ethylsuccinate.
Although the CL/F of erythromycin base generated from
erythromycin ethylsuccinate was superior to that generated
from estolate, they were not significantly different (1,595
versus 727 ml/min, respectively). Of interest is the finding
that of the 12 volunteers who received erythromycin esto-

TABLE 1. Pharmacokinetic parameters of erythromycin estolate (500 mg) and erythromycin ethylsuccinate (600 mg) after single and
multiple dosesa
Estolate Ethylsuccinate
Parameter
Single dose Multiple doses Single dose Multiple doses
Cm,, (,ug/ml) 3.08 ± 1.14 5.93 ± 2.34b 0.91 ± 0.69c 1.46 ± 0.68d
Tmax (h) 2.65 ± 1.23 2.02 ± 0.88 1.27 ± 0.49c 0.61 ± 0.21d
Ka (h-1) 0.96 ± 0.44 1.40 ± 0.69 2.16 ± 1.69 3.96 ± 2.03d
Half-life P (h) 3.04 ± 1.34 5.47 ± 2.24e 1.12 ± 0.90f 2.72 ± 1.49d,e
Vss/F (liters/kg) 2.11 ± 1.01 1.84 ± 1.10 7.76 ± 6.14c 8.94 ± 3.67d
AUC (,ug * h/ml)g 20.39 ± 12.0 30.61 ± 9.2 1.88 ± 1.20c 4.68 ± 1.51d
CL/F (ml/min) 572 ± 372 314 ± 154 7,502 ± 4,690" 2,415 ± 1,048e,h
CLR (ml/min) 5.0 ± 7.0 13.8 ± 10.2 42.3 ± 36.1c 22.4 ± 18.9
CLNR/F (ml/min) 567 ± 370 301 ± 147 7,459 ± 4,681c 2,392 ± 1,032
a Results are given as means ± standard deviations. Statistical analysis was done with Waller-Duncan's multiple-range test.
b
p < 0.01 (single dose versus multiple doses).
P < 0.01 (estolate single dose versus ethylsuccinate single dose).
d p < 0.01 (estolate multiple doses versus ethylsuccinate multiple doses).
e P
< 0.05 (single dose versus multiple doses).
f P < 0.05 (estolate single dose versus ethylsuccinate single dose).
g AUC is from 0 to infinity after a single dose or 0 to 8 h after the last dose of a multiple dose.
h P < 0.05
(estolate multiple doses versus ethylsuccinate multiple doses).
564 CROTEAU ET AL.
TABLE 2. Pharmacokinetic parameters of erythromycin base generated from the hydrolysis of estolate and ethylsuccinate after single
and multiple doses'
Estolate (erythromycin base)
Parameter
Single dose Multiple doses
Cmax (11 g/ml) 0.92 ± 0.80
Tmax (h) 2.7 ± 1.1
Half-life 1 (h) 4.33 ± 1.95
V,,/F (liters/kg) 4.53 ± 3.77
*
AUC (.g h/ml)g 6.14 ± 5.92 14.56 ± 7.04c
CL/F (mI/min) 1023 ± 449
CLR (ml/min) 33.6 ± 41.0
CLNR/F (ml/min) 989 ± 471
a See footnote a of Table 1.
b
p < 0.01 (single dose versus multiple doses).
c
P < 0.05 (single dose versus multiple doses).
d p < 0.05
(estolate multiple doses versus ethylsuccinate multiple doses).
e p < 0.05 (estolate single dose versus ethylsuccinate single dose).
f P < 0.01 (estolate multiple doses versus ethylsuccinate multiple doses).
9 See footnote g of Table 1.
h p < 0.01 (estolate single dose
versus ethylsuccinate single dose).
late, all had detectable levels of erythromycin base in plasma
12 h after the last dose, whereas 8 h after the last dose none
of the volunteers given erythromycin ethylsuccinate had
detectable levels of erythromycin base in plasma.
Diarrhea, abdominal pain, and cramps were mentioned
more frequently in volunteers receiving erythromycin esto-
late (n = 8) than in those given erythromycin ethylsuccinate
(n = 1). Mild liver abnormalities (elevations in alanine
transaminase [47 IU; normal is 0 to 24 IU] and aspartate
transaminase [41 IU; normal is 0 to 24 IU]) were observed in
one patient given 10 doses of erythromycin estolate. These
values returned to within normal limits 2 days later.
DISCUSSION
Numerous pharmacokinetics studies of erythromycin
esters have used assay methods that suffer major drawbacks,
including lack of specificity (5, 6) or elaborate sample
preparation (38). For this study we have developed a high-
pressure liquid chromatography assay that allows us to
measure directly and simultaneously concentrations of
erythromycin base and erythromycin estolate or erythromy-
cin ethylsuccinate.
Large variability among subjects after oral absorption of
erythromycin base preparations has been reported by sev-
eral investigators (17, 20, 27). This study has also demon-
strated substantial variability of the disposition of erythro-
mycin esters (3, 36, 37).
After a single dose, mean molar AUC ratios of erythro-
mycin base to total erythromycin (ester plus base) indicated
that 56 ± 34% of erythromycin ethylsuccinate circulated as
active erythromycin base, compared with 30 ± 23% for
erythromycin estolate. A similar pattern was observed at the
steady state, with 69 + 18% and 41 ± 11%, respectively.
Other investigators have reported comparable values (4, 39).
Moreover, in vitro half-life hydrolysis of erythromycin ethyl-
succinate in plasma at 37°C has been demonstrated to be
three times shorter than that of erythromycin estolate (55
versus 181 min) (12). In spite of this higher rate of transfor-
mation into active erythromycin base, the AUC of erythro-
mycin base generated from erythromycin ethylsuccinate at
the steady state was 1.6 times lower than that from erythro-
mycin estolate (P < 0.05). This may simply be explained by
a better bioavailability of the estolate. The absolute bioavail-
ability of erythromycin esters cannot be assessed directly:
erythromycin estolate and ethylsuccinate are not available
ANTIMICROB. AGENTS CHEMOTHER.
Ethylsuccinate (erythromycin base)
Single dose Multiple doses
2.62 ± 0.98b 0.58 ± 0.57 2.06 ± 1.52b
2.4 ± 1.2 2.5 ± 1.4 0.9 ± 0.8c,d
5.21 ± 2.92 1.54 ± 1.05e 5.83 ± 2.95c
3.25 ± 1.47 5.89 ± 4.67 10.0 ± 3.20bf
2.03 ± 1.93e 9.02 ± 4.90c.d
727 ± 456 4,119 ± 2,290" 1,595 ± 1,253b
45.6 ± 37.6 149.8 ± 107.3" 46.6 ± 47.1l
549 ± 171 3,969 ± 2,246h 1,188 ± 550b
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for intravenous administration. Nevertheless in this study,
data on the absorption of the estolate (Cmax, Tmax, and to
some extent AUC) exceeded those of ethylsuccinate, sug-
gesting greater bioavailability. Bechtol et al. reported also a
higher relative bioavailability for the base generated from the
estolate compared with that of the base generated from the
ethylsuccinate (4).
The half-life of erythromycin base when administered as
enteric-coating base has been reported between 1 and 2 h (7,
22, 27), but when erythromycin esters were administered as
in this study, the half-life of erythromycin base varied
between 1.54 and 5.83 h. In most cases, the apparent half-life
of erythromycin base was close to that of erythromycin
esters, suggesting that the elimination of erythromycin esters
and hence the formation of erythromycin base were rate
limiting (30).
Examination of the second peaks in the plasma concen-
tration-time curves of erythromycin esters and base revealed
that they occurred close to volunteers' midday meals. Bil-
iary recycling of erythromycin base has been demonstrated
(19) or suggested by different authors (2, 21, 23). This
phenomenon was seen but not commented on in other
papers (8, 18). Although biliary recycling of erythromycin
esters has not been demonstrated in humans due to poor
specificity of early assays toward erythromycin ethylsucci-
nate and erythromycin estolate (16, 19), these compounds do
possess the physicochemical properties required for the
occurrence of this phenomenon (molecular weight of >300,
high liposolubility, ionizable form) (9). Variations of gastro-
intestinal motility, gastric emptying, and intestinal transit
rate in the fasted state could also explain at least in part this
peculiar pharmacokinetic observation (29). Furthermore,
Shepard and co-workers have recently demonstrated that
the classical calculation of AUC for drugs subject to enterohe-
patic cycling is independent of cycling, a process making
clearance calculation valid (33).
This study emphasized the need for a specific high-pres-
sure liquid chromatography assay and the importance of
considering the wide variability, rate-limited processes, and
the appearance of a second peak when one studies erythro-
mycin ester kinetics. The pharmacokinetic data presented in
this study reinforce the clinical advantages of erythromycin
estolate over erythromycin ethylsuccinate. In fact, erythro-
mycin estolate twice a day was clinically and bacteriogically
more effective than ethylsuccinate in the treatment of strep-
VOL. 32, 1988 ADVANTAGE OF ERYTHROMYCIN ESTOLATE OVER ETHYLSUCCINATE
tococcal pharyngitis (13, 15, 16). Moreover, the lower ef-
ficacy of erythromycin ethylsuccinate may be explained by
undetectable erythromycin base concentration at 12 h. Ad-
ditional pharmacokinetic and efficacy studies should be
conducted in patients to further examine these data.
ACKNOWLEDGMENTS
We thank the nurses C. Beaudry and L. Lachapelle; we acknowl-
edge the critical comments of Michael Spino and Michael Dudley.
This work was supported in part by a grant from Eli Lilly Canada
Inc., Toronto, Ontario, Canada.
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