Pharmacokinetics of erythromycin after the administration of intravenous and various oral dosage forms to dogs.

The purpose of this study was to describe and compare the pharmacokinetic properties of different formulations of erythromycin in dogs. Erythromycin was administered as lactobionate (10 mg/kg, IV), estolate tablets (25 mg/kg p.o.) and ethylsuccinate tablets or suspension (20 mg/kg p.o.). After intravenous (i.v.) administration, the principal pharmacokinetic parameters were (mean +/- SD): AUC((0-infinity)) 4.20 +/- 1.66 microg x h/mL; C(max) 6.64 +/- 1.38 microg/mL; V(z) 4.80 +/- 0.91 L/kg; Cl(t) 2.64 +/- 0.84 L/h.kg; t((1/2)lambda) 1.35 +/- 0.40 h and MRT 1.50 +/- 0.47 h. After the administration of estolate tablets and ethylsuccinate suspension, the principal pharmacokinetic parameters were (mean +/- SD): C(max), 0.30 +/- 0.17 and 0.17 +/- 0.09 microg/mL; t(max), 1.75 +/- 0.76 and 0.69 +/- 0.30 h; t((1/2)lambda), 2.92 +/- 0.79 and 1.53 +/- 1.28 h and MRT, 5.10 +/- 1.12 and 2.56 +/- 1.77 h, respectively. The administration of erythromycin ethylsuccinate tablets did not produce measurable serum concentrations. Only the i.v. administration rendered serum concentrations above MIC(90) = 0.5 microg/mL for 2 h. However, these results should be cautiously interpreted as tissue erythromycin concentrations have not been measured in this study and, it is recognized that they can reach much higher concentrations than in blood, correlating better with clinical efficacy.

Pharmacokinetics of erythromycin estolate and erythromycin phosphate after intragastric administration to healthy foals.

OBJECTIVE: To determine pharmacokinetics and plasma concentrations of erythromycin and related compounds after intragastric administration of erythromycin phosphate and erythromycin estolate to healthy foals. ANIMALS: 11 healthy 2- to 6-month-old foals. PROCEDURE: Food was withheld from foals overnight before intragastric administration of erythromycin estolate (25 mg/kg of body weight; n = 8) and erythromycin phosphate (25 mg/kg; 7). Four foals received both drugs with 2 weeks between treatments. Plasma erythromycin concentrations were determined at various times after drug administration by use of high-performance liquid chromatography. Maximum plasma peak concentrations, time to maximum concentrations, area under plasma concentration versus time curves, half-life of elimination, and mean residence times were determined from concentration versus time curves. RESULTS: Maximum peak concentration of erythromycin A after administration of erythromycin phosphate was significantly greater than after administration of erythromycin estolate (2.9 +/- 1.1 microg/ml vs 1.0 +/- 0.82 microg/ml). Time to maximum concentration was shorter after administration of erythromycin phosphate than after erythromycin estolate (0.71 +/- 0.29 hours vs 1.7 +/- 1.2 hours). Concentrations of anhydroerythromycin A were significantly less 1 and 3 hours after administration of erythromycin estolate than after administration of erythromycin phosphate. CONCLUSIONS AND CLINICAL RELEVANCE: Plasma concentrations of erythromycin A remained > 0.25 microg/ml (reported minimum inhibitory concentration for Rhodococcus equi) for at least 4 hours after intragastric administration of erythromycin phosphate or erythromycin estolate, suggesting that the recommended dosage for either formulation (25 mg/kg, q 6 h) should be adequate for treatment of R equi infections in foals.

[Comparison of the bioavailabilities of erythromycin estolate and erythromycin ethylsuccinate dry suspension preparations in steady state]. / Vergleich der Bioverfügbarkeiten von Erythromycinestolat bzw. Erythromycinethylsuccinat enthaltenden Trockensaft-Zubereitungen im steady state.

Relative bioavailability of erythromycin was determined after multiple-dose administration of erythromycin estolate in comparison to erythromycin ethylsuccinate both given as oral suspensions to twelve healthy volunteers. The daily erythromycin dose of erythromycin ethylsuccinate was 50% higher than the respective dose of erythromycin estolate; the dosage interval tau was 12 h for erythromycin estolate and 8 h for erythromycin ethylsuccinate. This scheme was planned in accordance to advices of the respective manufactures. Results of the study confirm the differences in extent of bioavailability of both erythromycin derivatives known from single-dose investigations. Furthermore, the experimental data show that a twice daily administration of 1000 mg erythromycin as erythromycin estolat resulted in sufficiently high plasma concentration of the active compound.

Plasma bactericidal activity after administration of erythromycin estolate and erythromycin ethylsuccinate to healthy volunteers.

In a crossover design study, we compared the plasma bactericidal activities of erythromycin estolate (500 mg) and erythromycin ethylsuccinate (600 mg) after administration of a single oral dose to 12 healthy volunteers. Both erythromycin esters displayed very good plasma bactericidal activities against Streptococcus pneumoniae. The median bactericidal titers produced in plasma against Streptococcus pyogenes and Streptococcus pneumoniae were significantly higher with erythromycin estolate than with the ethylsuccinate ester at both 2 and 8 h after dosing (P less than 0.05 by Student's t test). Both erythromycin esters showed rather weak bactericidal activity against Branhamella catarrhalis; a further look at these results indicated that erythromycin estolate presented 50% of the plasma samples at 2 h with bactericidal titers superior or equal to 1:8, versus 11% for the ethylsuccinate ester. Of the 60 plasma bactericidal activity tests performed against Staphylococcus aureus, only 6 (10%) and 3 (5%) exhibited titers of 1:8 or greater for erythromycin estolate and erythromycin ethylsuccinate, respectively. Clinical trials are warranted in which these products are compared in infections other than Streptococcus pyogenes pharyngitis, for which the clinical superiority of erythromycin estolate has been demonstrated.

Pharmacokinetic advantages of erythromycin estolate over ethylsuccinate as determined by high-pressure liquid chromatography.

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 less than 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 micrograms/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.

High-performance liquid chromatographic assay of erythromycin and its esters using electrochemical detection.

A high-performance liquid chromatographic analysis of erythromycin and its esters in plasma, urine and saliva is presented. A diethyl ether extract of sample was chromatographed on a reversed-phase column and components of the column effluent were monitored by electrochemical detection at +0.9 V (vs. Ag/AgCl). The method sensitivity limit was 10 ng with inter-day coefficients of variation from 3.2 to 10.3%. In order to assess precisely the relative concentrations of erythromycin esters (ethylsuccinate or estolate) and their active by-product erythromycin base, it is necessary to adopt measures preventing their continuous hydrolysis in biological fluids and during sample preparation.

Pharmacokinetics of erythromycin ethylsuccinate and estolate in infants under 4 months of age.

We studied the pharmacokinetics of erythromycin estolate and ethylsuccinate suspensions in infants under 4 months of age who were being treated for chlamydial infections or pertussis. We conducted our studies after the initial dose of 10 mg/kg and subsequently during steady-state treatment. The estolate preparation resulted in higher peak concentrations in sera, and its absorption and elimination half-lives were longer. Peak concentrations occurred 3 h after a dose with the estolate preparation and 1 h after a dose with the ethylsuccinate preparation. The area under the curve for the estolate preparation was about three times greater than that for the ethylsuccinate preparation. Based on these findings, we recommend that erythromycin estolate suspensions be given to young infants at 8- or 12-h intervals (30 mg/kg per day in three divided doses or 20 mg/kg per day in two divided doses) and that erythromycin ethylsuccinate is best given at 6-h intervals (40 mg/kg per day in four divided doses).

Plasma levels following single and repeated doses of erythromycin estolate and erythromycin stearate.

The pharmacokinetics of erythromycin and erythromycin 2'-propanoate were studied in healthy male volunteers following single and repeated doses of erythromycin stearate tablets, erythromycin estolate capsules, and a suspension. Estolate dosages gave rise to higher plasma levels of total drug than the stearate. However, the stearate yielded higher plasma levels of erythromycin base. Absorption of all dosage forms, except the suspension, was delayed, and pharmacokinetic interpretation of both single- and multiple-dose data required incorporation of an absorption lag time. The absorption of erythromycin stearate was inhibited by food and also by low fluid volumes in fasted subjects. Absorption of erythromycin estolate was increased in the presence of food and was not greatly affected by fluid volume. Although single-dose data poorly predicted circulating levels of erythromycin following repeated doses, trends observed after single doses were maintained during chronic treatment.

Comparison of erythromycin base and estolate in gonococcal urethritis.

A randomized double-blind trial of 152 men with gonococcal urethritis compared the therapeutic efficacy of erythromycin estolate and erythromycin base. Twenty-one of 86 (24%) men treated with the estolate and 15 of 66 (23%) treated with the base had recurrent or persistent gonococcal infection when seen after a 9-g course of erythromycin. The serum erythromycin activity among estolate-treated patients (3.57 +/- 0.84 microgram/ml) was nearly twice that for base-treated patients (1.76 +/- 0.80 microgram/ml). Our findings do not support routine use of erythromycin for treatment of pregnant, penicillin-allergic patients.

Absorption of erythromycin. A cross-over study in healthy volunteers.

The absorptions of 6 erythromycin preparations were compared in a cross-over study in healthy humans. In a single-dose study, 500 mg of each preparation was, after an overnight fast, given to 10 volunteers. The two enterosoluble preparations of erythromycin base studied were absorbed slowly, and the peak serum concentration (1.5-2 mg/l) was achieved only at 4 h. The absorption of the stearates was quick, but especially one of them was poorly absorbed, the serum concentration being always below 1 mg/l. Both of the two estolates gave highest apparent concentrations, and the maximum serum level (2-2.5 mg/l) was achieved at 2 h, but the concentration of active erythromycin remains unknown. In the second part of the study, two erythromycin stearates and one base preparation were given at 6-h interval in a cross-over fashion, each for 4 days. On the 4th day, blood samples were analyzed. The erythromycin base gave higher serum concentrations than did the two stearates, which were equivalent. It seems doubtful that the erythromycin stearate at the dose of 250 mg every 6th hour would give satisfactory serum levels of erythromycin which would be effective against most bacteria during the whole treatment.

Metabolism of propionyl erythromycin lauryl sulfate. I. Fate of the propionyl erythromycin moiety in the rat.

The absorption, excretion, and metabolism of propionyl erythromycin (PE) has been studied in the rat. The major routes of metabolism of PE are ester hydrolysis and N-demethylation. The rates of these two reactions have been examined in vivo using radiolabeled PE. The plasma half-life of the ester is 5.5 hr. The correlation of blood levels of radioactivity with 14CO2 production indicates that the ester is continually hydrolyzed after absorption. The half-life of the dimethyl-amino moiety of the desosamine sugar is estimated at 1.5 hr. This relatively short half-life compared to that of the ester is supported by the fact that at 3.5 hr after dosing there is twice as much desmethyl-PE in plasma as PE. After oral administration of either 14C-PE or 14C-erythromycin, 70% of the radioactivity is absorbed in 6 hr. The major route of excretion is via bile. Approximatley 40% of the absorbed dose is excreted in bile in the first 6 hr after dosing. Tissue levels of radioactivity after administration of 14C-erythromycin or 14C-PE indicate that PE or a metabolite accumulates in the tissue during chronic dosing, whereas erythromycin-related levels are similar after single or multiple doses.