Pharmacokinetics of Single-Dose Erythromycin in Normal and

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1 ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Jan. 1982, p Vol. 21, No /82/ $02.00/0 Pharmacokinetics of Single-Dose Erythromycin in Normal and Alcoholic Liver Disease Subjects PATRICIA D. KROBOTH,l* ARNOLD BROWN,2 JAMES A. LYON,' FRANK J. KROBOTH,2 AND RANDY P. JUHL' Department ofpharmacy Practice, School ofpharmacy,1 and Department ofmedicine, School of Medicine,2 University of Pittsburgh, Pittsburgh, Pennsylvania Received 22 July 1981/Accepted 2 October 1981 Six normal males and eight male subjects with alcoholic liver disease (ALD) and ascites were given a single 500-mg dose of erythromycin base. Twelve serum samples were collected at 0, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, and 24 h after dosing and assayed microbiologically for erythromycin concentration. Absorption was characterized by a zero-order model for both groups. ALD subjects demonstrated a shorter lag time (2.0 versus 3.0 h), an earlier peak (4.6 versus 6.3 h, P < 0.05), and higher peak concentrations (2.04 versus 1.50,ug/ml) than normal subjects. Previously unreported biphasic elimination kinetics after oral dosing were observed in five normal and four ALD subjects. In the ALD group, the mean halflives for the first (a) and terminal (1B) phases were 1.6 and 4.5 h, respectively, and in normal subjects, were 1.3 and 6.6 h. The difference in a between groups was significant, P < The clinical significance of this finding for ALD patients receiving prolonged courses of erythromycin is discussed. Erythromycin has recently gained importance among antibiotics because of its use in the treatment of pneumonias due to Legionella pneumophila and other Legionella-like species. In normal subjects, only 2 to 5% (4) or less (5) of an oral dose is excreted in the urine in active form, whereas biliary erythromycin concentrations up to 800,ug/ml have been reported (15). Because of these observations, erythromycin is presumed to be eliminated mainly by the liver. Few data exist, however, on the influence of liver disease on the pharmacokinetics of erythromycin. Yet, in some clinical situations, as in the treatment of Legionnaires disease, there may be no reasonable alternative. In this paper, we describe a comparison of serum concentration-time data from normal and alcoholic liver disease (ALD) subjects after a single oral dose of erythromycin base. MATERIALS AND METHODS Six normal male subjects and eight male ALD subjects were selected for the study. The age and weight of each subject are provided in Table 1. After full disclosure of the protocol, informed, written consent was obtained. Subjects were denied entry into the study if they had received any antibiotic or antimetabolite within the previous 7 days or had received benzathine penicillin within 30 days preceding the study date. Subjects were also excluded if they had a history of intolerance to erythromycin formulations or had impaired renal function. A screening biochemical profile for each control subject was within normal limits. ALD was diagnosed by biopsy or by history, 135 symptoms, and signs. Only subjects with ascites but without encephalopathy, gastrointestinal bleeding, severe congestive heart failure, or prior shunting procedures were accepted for the study. Selected biochemical parameters for the ALD subjects are listed in Table 2. Subjects fasted 12 h before the study dose of erythromycin and drank only water until 4 h after the dose. Patients with ALD were permitted to take other medications as normally scheduled. At 8 a.m., two 250-mg enteric-coated tablets of erythromycin base (E-Mycin lot no. 161GC) were administered with 2 to 6 ounces (ca. 60 to 180 ml) of water. Venous blood samples were collected in anticoagulant-free vacuum tubes from a forearm vein before and 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, and 24 h after the dose. Sera were stored at -70 C until assayed. Assay. Serum samples were assayed for erythromycin concentration by a variation of the agar diffusion method described by Bell et al. (1). Each 100 ml of antibiotic medium no. 11, with ph adjusted to 8.0 ± 0.1 before autoclaving, was seeded with 0.1 ml of a suspension of Sarcina lutea (ATCC 9341) containing approximately 4.5 x 108 colony-forming units per ml. Antibiotic standards were prepared on the day of the assay, using erythromycin base, 936,ug activity per 1,000 pg (Upjohn; lot no. 935FD), in normal control serum (Ortho). The assay was linear from ag/ml to 4.0 p.g/ml. Serum samples were thawed only once and were assayed in quadruplicate. Four standards were used on each plate. Concentrations of erythromycin were determined from the standard curve for each plate. This was calculated by least-squares regression analysis of the logarithm of concentration versus zone diameter. The assay had a coefficient of variation (14) of 6.5% and a mean relative error (7) of 7.84%.

2 136 KROBOTH ET AL. Normal subjects TABLE 1. Demographic data ANTIMICROB. AGENTS CHEMOTHER. ALD subjects Subject ~ Age W Sbet Age Wt Subject (yr) (kg) Subject (yr) (kg) Mean Mean SD SD Pharmacokinetic and statistical methods. Using the for only 12 h. No zone of inhibition was obsemilogarithmic plot of the serum concentration ver- served around the 0-h disks of any subject. The sus time data for each subject, initial pharmacokinetic arithmetic means of serum concentrations obparameter estimates were determined by least-squares served at each sample time were calculated for regression and the method of residuals (3). The 24-h data were analyzed by first- and zero-order absorption the two groups (Fig. 1). The ALD group mean with one- and two-compartment open models. The concentrations were higher than those of the initial estimates of the pharmacokinetic parameters for control group at all sample times, but these each model were refined by NONLIN (10), a nonlinear differences were not statistically significant. iterative curve-fitting program, which simultaneously The maximum serum concentration observed analyzes the entire data set. The data were analyzed and the time of the maximum for each subject using a weight of 1/y2. The model with the highest along with the area under the serum concentracoefficient of determination (r2) was chosen. The area tion curve are shown in Table 3. Although the under the serum concentration curve was calculated maximum concentration and mean area under by the trapezoidal rule (3). To compare our results with previous studies, serum the curve were consistently higher in the ALD concentration-time data from the first 12 h after the group, the differences between groups were not dose were analyzed by a zero-order absorption one- statistically significant. However, the observed conmpartment open model. In all instances, the two- mean time of the maximum in the ALD group, tailed Student's t-test was used to test significance of 4.1 h, was earlier than in the normal group, 6.3 the differences between normal and ALD groups. h. These values agree closely with the NON- LIN-generated estimates of the actual times of RESULTS the maximum, which were 4.6 and 6.3 h after the Six normal and six ALD subjects were studied dose for the groups, respectively. These differduring the 24 h after erythromycin administra- ences were statistically significant (P < 0.05). tion; two additional ALD subjects were studied Of the 14 subjects, 6 had three or more TABLE 2. Selected biochemical parameters: ALD subjects Albumin Bilirubin SGOP SGPTb Prothrombin Blood urea Serum Subject (gtloo ml) (mg/100 ml) Utliter U/liter time (s) nitrogen creatinine direct/total Control/patient (mg/100 ml) (mg/too ml) / / / / c / / / / / / / / c / / c / / Normal range / a Serum glutamic b oxalacetic transaminase. Serum glutamic pyruvic transaminase. c Patient had liver biopsies demonstrating Laennec's cirrhosis.

3 VOL. 21, 1982 oh HOUR3 FIG. 1. Mean serum erythromycin concentrations after a single 500-mg oral dose. Circles represent ALD subjects, triangles represent normal subjects. Bars indicating standard errors of the means are drawn in only one direction to prevent overlap. concentration-time data points in the absorption phase which allowed characterization of absorption. Based on the r2 value obtained for the two models, a better fit was obtained with a zeroorder as compared with a first-order absorption SINGLE-DOSE ERYTHROMYCIN IN ALD SUBJECTS 137 model (data not shown). There was, however, considerable intersubject variability in the zeroorder absorption term, kofiv, where ko is the absorption rate constant, F is the fraction absorbed, and V is the volume of distribution. All subjects demonstrated a delay before erythromycin concentrations could be detected in the serum. Lag times of 3.0 h in the normal group and 2.0 h in the ALD group were observed, although this difference was not statistically significant. The pharmacokinetic parameters resulting from NONLIN curve fitting are given in Tables 4 and 5. evaluation of the data, using a onecompartment open model and assuming zeroorder absorption, resulted in a good fit for control subject 1 and ALD subjects 8 and 9. When data from the other nine subjects were analyzed with this model, the predicted concentrations for the terminal phase deviated from the actual concentrations by up to 86%, despite relatively high r2 values. For these five normal and four ALD subjects, a two-compartment open model resulted not only in a better correlation of actual and predicted serum concentrations, but also a higher r2 value. In normal subjects, the mean half-life of the first phase of disappearance (a) from serum was 1.3 h followed by a terminal phase (,) half-life of 6.6 h. In the ALD group, TABLE 3. Model independent pharmacokinetic parameters Crnaxa Tmab AUCc AUC Subject (>giml) T(h) (>g.h/ml) --*12 (>g.h/ml) Subject (h) ~~~~~~~~0 Normal Mean SD ±0.91 t0.8 ± 5.1 ± 5.9 ALD d Mean e SD ± ± 7.8 ± 8.9 a Maximum serum concentration observed. b Time of observed maximum concentration. c AUC, Area under the serum concentration curve. d -, Subjects were not studied after 12 h. etmax of ALD group significantly different from normal group, P <

4 138 KROBOTH ET AL. TABLE 4. Pharmacokinetic parameter estimates: one-compartment open model with zero-order absorption Subject k0f/va Lag Tmaxb k t1/2 r2 Normal ALD a Zero-order absorption term: ko is the absorption rate constant, F is the fraction absorbed, and V is the volume of distribution. b Estimated time of maximum serum concentration. the mean half-lives for the first and terminal phases were 1.6 and 4.5 h, respectively. The difference in a between the ALD and normal groups was statistically significant. DISCUSSION This study was designed to compare the pharmacokinetics of single-dose erythromycin in normal and ALD subjects. Findings in this study disclosed information previously unreported for either group. Normal subjects. Although other investigators have reported a delay before absorption begins, a longer lag time was found in the present investigation. This difference may be due to the TABLE 5. ANTIMICROB. AGENTS CHEMOTHER. prolonged fasting period of our subjects, which extended from 12 h before the dose to 4 h after the dose. In other studies, subjects fasted for only 2 to 8 h followed by a post-dose fast of only 1 to 3 h (2, 9, 16). The extended pre- and postdosing fast used in this study may have resulted in slower gastric emptying and thus slower delivery of the antibiotic to its absorption site in the intestine. Despite the length of the lag time, the mean observed maximum concentration of 1.5 jxg/ml after a single 500-mg dose was comparable to that of other studies. This study also confirms previous reports that a zero-order process more accurately describes erythromycin absorption after a single dose than does a first-order process (2, 16). The intersubject variability in the zero-order absorption term, kofiv, was not surprising, since the fraction absorbed, F, is known to vary considerably among subjects (12). Previously, the half-life of a single-dose erythromycin elimination was reported to be 1.8 to 2.0 h when serum concentrations were studied during the 6 h after drug administration (2, 9, 16). Using a 12-h post-dose sampling period, Welling et al. (16) reported a mean half-life of 3.5 h. For comparison, when data from the first 12 h of the present study were analyzed by a onecompartment model, the mean elimination halflife was found to be 2.28 h, which agrees with previous reports. However, we continued sampling for 24 h, and analysis of the data from most Pharmacokinetic parameter estimates: two-compartment open model with zero-order absorption Subject VIP' (L) Lag (h) Tmaxb a k21 (h-1) r2 Normal 1 -C Mean SD 34.2 ±1.5 ±1.4 ±0.071d ALD Mean SD ±88.9 ±0.7 ±1.8 ±0.050 ±0.054 ±0.068 a Where V is the volume of distribution and F is the fraction absorbed. b Estimated time of maximum serum concentration. c, Serum concentration-time data from this subject more appropriately described by one-compartment model with zero-order absorption. d The differences between the means of normal and ALD groups were significant at P < 0.05.

5 VOL. 21, 1982 normal subjects for the 24-h period clearly demonstrated biphasic elimination. Therefore, erythromycin elimination is not as rapid as previously thought. The existence of this slow elimination phase of erythromycin is supported by other indirect evidence. Erythromycin has been recovered in fecal samples 3.5 days after a dose (11). Presumably, this erythromycin was slowly released from tissues where it is thought to bind (17) and was then excreted from the central compartment. Enterohepatic recycling (6) may also have contributed to the presence of erythromycin in the fecal samples. In addition, investigators have found that maximum serum concentrations after repeated doses of erythromycin exceed those predicted from single-dose data by a factor of nearly two (2, 9, 16). It has been suggested that more drug is absorbed with repeated doses. This could be explained by enterohepatic recycling or by a change in the absorption process. The slower elimination of erythromycin observed in our study would also contribute to accumulation of the drug. Thus, biphasic elimination after oral dosing must be considered an additional explanation of the elevated steadystate serum concentrations that have been described. ALD subjects. Few published data exist about the pharmacokinetics of erythromycin in subjects with ALD. Examination of the maximum serum concentrations observed in Table 1 reveals that some ALD subjects achieved very high serum concentrations after this single 500- mg dose. Also, from Fig. 1 it can be seen that the differences in mean serum concentrations are most striking early in the time course. When coupled with the longer initial half-life observed in this study, this would indicate that some ALD subjects may accumulate erythromycin to excessive concentrations during a therapeutic course. In four of the eight ALD subjects there were sufficient data to characterize absorption. As in the normal group, the data correlated better with a zero-order absorption model. However, a shorter lag time and an earlier peak were observed in the ALD subjects. The reverse was expected since the absorption of erythromycin stearate has been shown to be delayed in recumbent subjects (13), and most of the ALD subjects were at bed rest, whereas the controls were ambulatory. In addition, absorption of another antibiotic, ampicillin, is slower in cirrhotic subjects than in normal volunteers, with peak concentrations occurring 1.5 to 4.5 h later than in normals (8). Hence, the present findings of more rapid erythromycin absorption in the ALD group were unprecedented and cannot be explained. SINGLE-DOSE ERYTHROMYCIN IN ALD SUBJECTS 139 When the data from eight ALD subjects for the first 12 h were compared with those from normals for this same period, an elimination rate significantly slower than that of the controls was observed. This agrees with the findings of Hall et al. (Clin. Pharmacol. Ther., in press) which would imply that elimination was impaired. However, when the serum concentrations were evaluated for 24 h after the dose, other possibilities became apparent. Not only might there be impaired early elimination of erythromycin, but an altered rate of exchange between compartments is likely. In summary, we conclude that single-dose erythromycin absorption follows a zero-order absorption model in both normal and ALD subjects and that ALD subjects have a shorter lag time and an earlier time of peak concentration than controls. Biphasic elimination kinetics were observed for most normal and ALD subjects, with a significantly slower a phase in the ALD group. At all sample times, ALD subjects had higher mean serum concentrations than normal subjects. Whether an alteration in dosage is necessary in patients with ALD cannot be answered definitively until the steady-state pharmacokinetics and relative safety of erythromycin are studied in this group. The present study suggests that in ALD patients, steady-state serum concentrations higher than usual would be achieved. This may be significant and require dosage adjustment, especially during long courses of erythromycin therapy. ACKNOWLEDGMENT We express our appreciation to Richard Vickers and John Rihs for their expert technical assistance with the microbiological assay. LITERATURE CITED 1. Bell, S. C., J. Hamman, and W. E. Grundy Micromethod for assaying serum levels of erythromycin. Appl. Microbiol. 17: Colburn, W. A., A. R. DiSanto, and M. Gibaldi Pharmacokinetics of erythromycin on repetitive dosing. J. Clin. Pharmacol. 17: Gibaldi, M., and D. Perrier Appendices 3 and 4, p %. In Pharmacokinetics. Marcel Dekker, Inc., New York. 4. Griffith, R. S., and H. R. Black Erythromycin. Pediatr. Clin. North Am. 8: Haight, T. H., and M. Finland The antibacterial action of erythromycin. Proc. Soc. Exp. Biol. Med. 81: Hammond, J. B., and R. S. 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