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.

Variability in the absorption and disposition of erythromycin estolate in humans.

The inter- and intrapersonal variability in the absorption and disposition of erythromycin estolate in humans was assessed by comparing total erythromycin serum concentrations in five subjects who each received a single erythromycin estolate tablet on three separate occasions under identical experimental conditions. Coefficients of variation for the pharmacokinetic parameters Cmax, Tmax, AUC0-12, MRT, and t1/2 were of a similar magnitude when calculated between subjects in any one administration phase or between phases. In addition, serum concentrations of both erythromycin base (active component) and erythromycin propionate were selectively determined in the same subjects only during the final two phases of the study. Comparison of AUC0-12 values showed that the percentage of the total area (base and ester components) present as erythromycin base remained relatively constant between administrations (mean values of 14.5 and 11.2%), with low coefficients of variation between subjects (10.8 and 11.6%). Discrepancy value calculations revealed that the variability in serum concentration-time profiles between the three phases of the study fell into the "small"-to-"moderate" classification. From these data it is apparent that intrapersonal variations in the absorption and disposition of erythromycin estolate are of a similar magnitude to interpersonal variations and should be borne in mind in the design and interpretation of comparative bioavailability studies involving similar formulations of this compound. The relative proportions of erythromycin base and propionate did, however, remain fairly constant both between treatments and between subjects.

Toxicity, uptake, and subcellular distribution in rat hepatocytes of roxithromycin, a new semisynthetic macrolide, and erythromycin base.

Rat hepatocytes were used to study the toxicity of a new semisynthetic macrolide, roxithromycin, in comparison with erythromycin base and erythromycin estolate. Roxithromycin caused lactate dehydrogenase leakage close to that of erythromycin estolate and higher than erythromycin base after 21 h of exposure to the drugs. This effect was, at least in part, explained by the higher uptake: roxithromycin was two to three times more concentrated by liver cells than erythromycin base. For both roxithromycin and erythromycin base, the uptake depended on time, temperature, and extracellular antibiotic concentration. The accumulated macrolides egressed rapidly when cells were incubated in antibiotic-free medium. No uptake and no loss of accumulated drugs were observed at 4 degrees C. After accumulation by hepatocytes, roxithromycin and erythromycin base underwent similar subcellular distribution, mostly concentrating in cytosol and lysosomes. The small amount accumulated in the other particulate fractions followed the order mitochondria much greater than nuclei greater than microsomes. Roxithromycin, however, was less concentrated than erythromycin base in the microsomes.

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.