Vol. 32, No. 4ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Apr. 1988, p. 561-5650066-4804/88/040561-05$02.0O/OCopyright C 1988, American Society for Microbiology

Pharmacokinetic Advantages of Erythromycin Estolate overEthylsuccinate as Determined by High-Pressure

Liquid ChromatographyDANIEL 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

The pharmacokinetics of erythromycin estolate (500 mg) and erythromycin ethylsuccinate (600 mg) werecompared in 12 healthy volunteers after single doses and after repeated oral doses (every 8 h). High-pressureliquid chromatography with electrochemical detection was used to determine concentrations in plasma andurine of estolate, ethylsuccinate, and erythromycin base. The maximum concentration of drug in the serum, thehalf-life, and the area under the curve for erythromycin estolate were significantly greater than those oferythromycin ethylsuccinate after both regimens. After single and multiple doses, the respective areas underthe curve of erythromycin base generated by estolate formulation were 3 and 1.6 times greater (P < 0.05) thanthose of ethylsuccinate. The lower percentage of hydrolysis of erythromycin estolate (41 versus 69%) combinedwith 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 specifichigh-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 oferythromycin esters. The pharmacokinetic data presented in this study reinforce the clinical advantages oferythromycin estolate over erythromycin ethylsuccinate.

Recent clinical trials suggest that erythromycin estolate ismore effective than erythromycin ethylsuccinate in the treat-ment of streptococcal pharyngitis (13, 15), even at a lowerdosage (16). To be active, the esters of erythromycin need tobe hydrolyzed to erythromycin base (35). Higher concentra-tions in plasma of erythromycin base resulting from apurported better absorption of erythromycin estolate hasoften been evoked to explain these differences (11, 14, 28).Higher levels of erythromycin estolate in plasma have alsobeen suggested to be artifacts of the bioassay itself (28).Thus, resolution of this controversy has been delayed by thelack of a specific assay that can provide valuable pharmaco-kinetic data on erythromycin estolate, ethylsuccinate, andtheir respective erythromycin bases (14). The purpose of thisstudy was to compare concentrations in plasma of erythro-mycin estolate (500 mg), erythromycin ethylsuccinate (600mg), and their respective bases in healthy adult volunteersafter administration of single and multiple doses by using ahigh-pressure liquid chromatography assay with electro-chemical detection.

MATERIALS AND METHODSSubjects 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 informedconsent to participate in the study. The protocol was ap-proved by the Centre Hospitalier de l'Universitd LavalHuman Research Review and Pharmacology-TherapeuticsCommittees. The mean weight of the subjects was 69.2 ± 9.8kg (range, 53.5 to 87.0 kg). All subjects were judged to behealthy on the basis of history, physical examination, chem-istry profile, complete blood count, and urinalysis. None hada history of hepatic, renal, or neoplastic disease or known

* Corresponding author.

previous allergy to macrolide compounds. No medicationwas allowed at the time of study, and alcoholic beverageswere withheld 24 h before and during the study. Volunteershad to refrain from any strenuous or athletic activity duringthe study period but were allowed to circulate around thepharmacokinetic 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) orerythromycin ethylsuccinate (600 mg of base equivalent;Laboratoires Abbott Limitde, Montreal) taken with 150 ml ofdrinking water. Starting on the morning of day 5 andcontinuing through day 7, each volunteer was instructed totake (in an outpatient environment) nine consecutive doses(every 8 h) of the same drug as on day 1 in a fasting state. A1-h fast before or a 2-h fast after drug administration wasdictated during this multiple-dosage regimen. A final dosewas given on the morning of day 8 with at least 150 ml ofdrinking water after an overnight fast. Each subject wasstudied 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 hafter a single dose. After the last dose, additional blood wasdrawn at 24 h. A dilute heparin solution (33 U/ml) was usedto maintain patency of the catheter, and at least 1.5 ml ofblood 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 bloodsample was immediately placed into an ice bath until it was

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10 -

z0w0z0

0 1 2 3 4 5 6 7 8 9 10 11 12

TIME (HOURS)

FIG. 1. Concentrations in plasma of erythromycin estolate (500-mg dose) (0) and erythromycin base (0) after a single dose in onetypical volunteer.

spun in a refrigerated centrifuge (900 x g, 10 min). Thecollected plasma was then frozen at -20°C until assayed.

Urine was collected immediately before dose 1 and then atintervals between 0 and 2, 2 and 4, 4 and 8, and 8 and 12 hafter 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-pressureliquid chromatography procedure with electrochemical de-tection developed in our laboratory (12). Briefly, separationof erythromycin base, roxithromycin (internal standard),and erythromycin estolate or erythromycin ethylsuccinatewas achieved by using electrochemical detection at +0.9 V(against Ag-AgCl) and a NovaPak C18 column (WatersScientific, Mississauga, Ontario, Canada). The mobile phaseconsisted of 56% sodium acetate buffer (56 mM-40%acetonitrile-4% methanol, adjusted to pH 7.0 and pumped at1.1 ml/min. Retention times were 6.0, 14.7, 34.7, and 35.4min, 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 thesample, 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

E

z0

c-zw0z00)

1-

ECD

z0I-

zwz00

1 2 3 4 5 6 7 8 9 10 11 12

E

z0

c-zw0z00

1-

o.yo.o.-o

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

FIG. 3. Concentrations in plasma of erythromycin estolate (500-mg dose) (@) and erythromycin base (0) after multiple doses (every8 h) in one typical volunteer.

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, and0.987 for erythromycin base (0 to 10 p.g/ml), erythromycinestolate (0 to 10 ,ug/ml), and erythromycin ethylsuccinate (0to 3 ,ug/ml), respectively.

Pharmacokinetic analysis. Because of the appearance of asecond peak in the curves of level in plasma versus time,noncompartmental pharmacokinetic analysis was used (Fig.1 through 4). The absorption constant (Ka) was obtainedfrom Pharm I by using the method of residuals (25). Theelimination constant (kel) was derived from linear regressionof the terminal log-linear portion of individual plots ofconcentration in plasma versus time.The area under the curve of concentration in plasma

versus time (AUC) from time zero to infinity (AUC,OO) wascalculated with conventional linear trapezoidal and extrap-olation methods. The apparent total clearance (CL/F) oferythromycin base or erythromycin esters was estimatedfrom the following model-independent pharmacokineticequations: CL/F = dose/AUC., for a single dose and CL/F= dose/AUCO_8 h after the last dose (where 8 h is theinterval). To simplify comparisons, the same dose (500 or600 mg) was used for erythromycin base and erythromycin

TIME (HOURS)

FIG. 2. Concentrations in plasma of erythromycin ethylsucci-nate (600-mg dose) (0) and erythromycin base (0) after a single dosein one typical volunteer.

TIME (HOURS)FIG. 4. Plasma concentrations of erythromycin ethylsuccinate

(600-mg dose) (0) and erythromycin base (0) after multiple doses(every 8 h) in one typical volunteer.

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esters in the calculation of CL/F. Renal clearance (CLR) wascalculated by using the following relationship: CLR= Ae (t1- t2)/AUC (t1 - t2), where Ae is the amount of erythromycinbase, erythromycin estolate, or erythromycin ethylsuccinateeliminated unchanged in urine from time t1 to t2. Theapparent nonrenal clearance (CLNR/F) was estimated bysubtracting CLR from CL/F. Note that CLNR/F of the estersinvolves both elimination from the body and hydrolysis toerythromycin base. The apparent volume of distribution atsteady state (V1r5/F) after a single dose was calculated fromthe following relationship: V551F = (dose AUMC/AUC2) -

(dose/KaAUC) (31), where AUMC is the area under the firstmoment 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 equalto 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 ofplasma pharmokinetic parameters. The Wailer-Duncan testwas used to compare the means (32). A P of <0.05 wasconsidered statistically significant.

RESULTS

Levels of erythromycin base and erythromycin estolate orerythromycin ethylsuccinate in plasma from four typicalvolunteers are presented in Fig. 1 to 4. Individual patientsevidenced concentration curves in plasma with humps thatwere no longer identifiable in the mean-value curves ob-tained by combining the individual curve and superposingthe 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 occurredabout 1 h later than the peak for erythromycin ethylsuccinate(2.65 ± 1.23 versus 1.27 ± 0.49 h). Eight hours afteradministration of a single dose, erythromycin ethylsuccinatewas undetectable in plasma in all 12 volunteers, whereaserythromycin estolate was still present after 12 h in allvolunteers. After dose 10, the erythromycin estolate peakconcentration was higher than it was after a single dose, asanticipated from pharmacokinetic theory (P < 0.01). At 24 h

after dose 10, erythromycin estolate was still detectable infour volunteers compared with only one volunteer with theethylsuccinate form.The pharmacokinetic parameters estimated from plasma

concentration data for erythromycin estolate and erythromy-cin ethylsuccinate are listed in Table 1. The mean absorptionrate 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 estolatewas eliminated more slowly than erythromycin ethylsucci-nate (half-life, 3.04 versus 1.12 h after a single dose and 5.47versus 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 largerVSs/F than estolate after single (8.94 versus 1.84 liters per kg;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 singledose (AUCOC, 20.39 versus 1.88 ,ug. h/ml; P < 0.01) andmultiple doses (AUCOJ8 h, 30.61 versus 4.68 ug * h/ml; P <0.01). In fact, erythromycin ethylsuccinate was cleared fromthe body 8 to 15 times more rapidly than erythromycinestolate as shown by their CL/Fs after both a single dose(7,502 versus 572 ml/min) and multiple doses (2,415 versus314 ml/min). Multiple dose administration did not seem toaffect significantly CLR of erythromycin estolate but greatlyreduced that of erythromycin ethylsuccinate after the lastdose 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. Aftera single dose there was no significant difference between theCmax, Tmax, and volume of distribution of erythromycin basegenerated 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

1.6 times greater (14.56 versus 9.02 ug - h/ml; P < 0.05) thanthat of base derived from erythromycin ethylsuccinate.Although the CL/F of erythromycin base generated fromerythromycin ethylsuccinate was superior to that generatedfrom estolate, they were not significantly different (1,595versus 727 ml/min, respectively). Of interest is the findingthat of the 12 volunteers who received erythromycin esto-

TABLE 1. Pharmacokinetic parameters of erythromycin estolate (500 mg) and erythromycin ethylsuccinate (600 mg) after single andmultiple dosesa

Estolate EthylsuccinateParameter

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 ± 0.68dTmax (h) 2.65 ± 1.23 2.02 ± 0.88 1.27 ± 0.49c 0.61 ± 0.21dKa (h-1) 0.96 ± 0.44 1.40 ± 0.69 2.16 ± 1.69 3.96 ± 2.03dHalf-life P (h) 3.04 ± 1.34 5.47 ± 2.24e 1.12 ± 0.90f 2.72 ± 1.49d,eVss/F (liters/kg) 2.11 ± 1.01 1.84 ± 1.10 7.76 ± 6.14c 8.94 ± 3.67dAUC (,ug * h/ml)g 20.39 ± 12.0 30.61 ± 9.2 1.88 ± 1.20c 4.68 ± 1.51dCL/F (ml/min) 572 ± 372 314 ± 154 7,502 ± 4,690" 2,415 ± 1,048e,hCLR (ml/min) 5.0 ± 7.0 13.8 ± 10.2 42.3 ± 36.1c 22.4 ± 18.9CLNR/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).

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TABLE 2. Pharmacokinetic parameters of erythromycin base generated from the hydrolysis of estolate and ethylsuccinate after singleand multiple doses'

Estolate (erythromycin base) Ethylsuccinate (erythromycin base)Parameter

Single dose Multiple doses Single dose Multiple doses

Cmax (11 g/ml) 0.92 ± 0.80 2.62 ± 0.98b 0.58 ± 0.57 2.06 ± 1.52bTmax (h) 2.7 ± 1.1 2.4 ± 1.2 2.5 ± 1.4 0.9 ± 0.8c,dHalf-life 1 (h) 4.33 ± 1.95 5.21 ± 2.92 1.54 ± 1.05e 5.83 ± 2.95cV,,/F (liters/kg) 4.53 ± 3.77 3.25 ± 1.47 5.89 ± 4.67 10.0 ± 3.20bfAUC (.g * h/ml)g 6.14 ± 5.92 14.56 ± 7.04c 2.03 ± 1.93e 9.02 ± 4.90c.dCL/F (mI/min) 1023 ± 449 727 ± 456 4,119 ± 2,290" 1,595 ± 1,253bCLR (ml/min) 33.6 ± 41.0 45.6 ± 37.6 149.8 ± 107.3" 46.6 ± 47.1lCLNR/F (ml/min) 989 ± 471 549 ± 171 3,969 ± 2,246h 1,188 ± 550b

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).fP < 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 plasma12 h after the last dose, whereas 8 h after the last dose noneof the volunteers given erythromycin ethylsuccinate haddetectable levels of erythromycin base in plasma.

Diarrhea, abdominal pain, and cramps were mentionedmore frequently in volunteers receiving erythromycin esto-late (n = 8) than in those given erythromycin ethylsuccinate(n = 1). Mild liver abnormalities (elevations in alaninetransaminase [47 IU; normal is 0 to 24 IU] and aspartatetransaminase [41 IU; normal is 0 to 24 IU]) were observed inone patient given 10 doses of erythromycin estolate. Thesevalues returned to within normal limits 2 days later.

DISCUSSIONNumerous pharmacokinetics studies of erythromycin

esters have used assay methods that suffer major drawbacks,including lack of specificity (5, 6) or elaborate samplepreparation (38). For this study we have developed a high-pressure liquid chromatography assay that allows us tomeasure directly and simultaneously concentrations oferythromycin 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) indicatedthat 56 ± 34% of erythromycin ethylsuccinate circulated asactive erythromycin base, compared with 30 ± 23% forerythromycin estolate. A similar pattern was observed at thesteady state, with 69 + 18% and 41 ± 11%, respectively.Other investigators have reported comparable values (4, 39).Moreover, in vitro half-life hydrolysis oferythromycin ethyl-succinate in plasma at 37°C has been demonstrated to bethree times shorter than that of erythromycin estolate (55versus 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 atthe steady state was 1.6 times lower than that from erythro-mycin estolate (P < 0.05). This may simply be explained bya better bioavailability of the estolate. The absolute bioavail-ability of erythromycin esters cannot be assessed directly:erythromycin estolate and ethylsuccinate are not available

for intravenous administration. Nevertheless in this study,data on the absorption of the estolate (Cmax, Tmax, and tosome extent AUC) exceeded those of ethylsuccinate, sug-gesting greater bioavailability. Bechtol et al. reported also ahigher relative bioavailability for the base generated from theestolate compared with that of the base generated from theethylsuccinate (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 asin this study, the half-life of erythromycin base variedbetween 1.54 and 5.83 h. In most cases, the apparent half-lifeof erythromycin base was close to that of erythromycinesters, suggesting that the elimination oferythromycin estersand hence the formation of erythromycin base were ratelimiting (30).Examination of the second peaks in the plasma concen-

tration-time curves of erythromycin esters and base revealedthat 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). Thisphenomenon was seen but not commented on in otherpapers (8, 18). Although biliary recycling of erythromycinesters has not been demonstrated in humans due to poorspecificity of early assays toward erythromycin ethylsucci-nate and erythromycin estolate (16, 19), these compounds dopossess the physicochemical properties required for theoccurrence of this phenomenon (molecular weight of >300,high liposolubility, ionizable form) (9). Variations of gastro-intestinal motility, gastric emptying, and intestinal transitrate in the fasted state could also explain at least in part thispeculiar pharmacokinetic observation (29). Furthermore,Shepard and co-workers have recently demonstrated thatthe classical calculation ofAUC for drugs subject to enterohe-patic cycling is independent of cycling, a process makingclearance calculation valid (33).

This study emphasized the need for a specific high-pres-sure liquid chromatography assay and the importance ofconsidering the wide variability, rate-limited processes, andthe appearance of a second peak when one studies erythro-mycin ester kinetics. The pharmacokinetic data presented inthis study reinforce the clinical advantages of erythromycinestolate over erythromycin ethylsuccinate. In fact, erythro-mycin estolate twice a day was clinically and bacteriogicallymore effective than ethylsuccinate in the treatment of strep-

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tococcal pharyngitis (13, 15, 16). Moreover, the lower ef-ficacy of erythromycin ethylsuccinate may be explained byundetectable erythromycin base concentration at 12 h. Ad-ditional pharmacokinetic and efficacy studies should beconducted 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 CanadaInc., Toronto, Ontario, Canada.

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