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Effect of food on absorption of erythromycin acistrate (2'-acetyl erythromycin stearate, Erasis; CAS 96128-89-1) was studied in 14 healthy volunteers in a randomized cross-over design. The subjects were given 400 mg erythromycin acistrate enteric coated tablets b.i.d. for 4 days. On the 1st and 4th days the tablets were taken after an overnight fast or immediately after a light or a heavy breakfast. Erythromycin (E), 2'-acetyl-erythromycin (2AE), anhydroerythromycin and anhydro-2'-acetyl-erythromycin concentrations in plasma were analyzed chemically by HPLC. After a single dose the lag time of absorption (tlag) was significantly longer after both types of breakfasts as compared to fast. The tmax of E and 2AE were also somewhat delayed by food although tmax of 2AE after a heavy breakfast only differed statistically significantly from that of the fasting state. Food significantly delayed the absorption especially in some subjects since no drug was observed during the 12-h observation period in 2 and 5 of the subjects after a light and heavy breakfast, respectively. At steady state the delaying effect of food on absorption had almost disappeared. No significant differences were observed in Cmax- or AUC0-12-values between the fasting and the fed states both after a single dose or at steady state. It is concluded, that food does not affect the mean bioavailability of erythromycin acistrate neither the mean rate of absorption but in some subjects the absorption from enteric coated tablets might be significantly delayed.

The drug concentration in plasma, suction skin blister fluid (SBF), urine and saliva after repeated dosage of either erythromycin acistrate (EA) or enterocoated pellets of erythromycin base (EB) was studied in young healthy volunteers with a cross-over design in two separate studies. In Study I, the total drug concentration (erythromycin + 2'-acetyl erythromycin) after EA (400 mg tid) was slightly higher than the erythromycin concentration after EB (500 mg tid). The concentration of erythromycin after EA was about half of that after EB. In SBF the total antibiotic concentration after EA and erythromycin concentration after EB were 49 and 46% of the corresponding plasma concentrations, respectively. The degree of hydrolysis of 2'-acetyl erythromycin was higher in SBF (44%) than in plasma (39%). An equal proportion (7.3-7.5%) of the dose was excreted in urine after administration of both drugs. The degree of hydrolysis of 2'-acetyl erythromycin in urine was 58%. In Study II, the plasma/saliva concentration ratio ranged from 0.11 to 0.17 after EA 400 mg tid, 0.12 to 0.20 after EA 500 mg tid and 0.17 to 0.22 after EB 500 mg tid. The degree of hydrolysis of 2'-acetyl erythromycin was considerably higher in saliva (61-78%) than in plasma (27-41%). In plasma, the percentage of hydrolysis of 2'-acetyl erythromycin was inversely correlated with the concentration of acid-alpha 1-glycoprotein. The penetration of 2'-acetyl erythromycin and erythromycin into the extravascular space as evaluated from SBF and saliva levels was equal, and adequate concentrations of erythromycin were obtained for the treatment of bacterial infections.(ABSTRACT TRUNCATED AT 250 WORDS)

Concentrations of erythromycin and 2'-acetyl erythromycin were analysed in serum or plasma and tonsil tissue after repeated dosage of erythromycin acistrate (EA), a new erythromycin prodrug, in two separate studies in 61 young patients. The reference preparations were: (1) enterocoated tablets of erythromycin base (EB enterotablets, (2) erythromycin base as enterocoated pellets (EB enterocapsules) and (3) erythromycin stearate (ES). All drugs were given 500 mg tid for three days before scheduled tonsillectomy. Tonsils were removed about 3 h after intake of the last dose. Blood samples were collected at 0, 2 and 6 h and at the time of tonsillectomy. At all time points EA produced several-fold higher total drug (erythromycin + 2'-acetyl erythromycin) concentrations in serum or plasma than any of the reference preparations. Similarly, after EA the mean total antibiotic levels in tonsil tissue exceeded the erythromycin levels after the reference preparations by at least a factor of 3. Tonsil/serum or plasma ratios of the total antibiotic were quite similar with all preparations (means 38-50%). Peak erythromycin levels in circulation did not differ significantly from each other in spite of two nonabsorbers after EB enterotablets. The same was true of tonsil tissue. There were, however, 15 tonsils with undetectable erythromycin: 4/25 (16%) with EA, 5/12 (42%) with EB enterotablets, 2/12 (17%) with EB enterocapsules and 4/12 (33%) with ES. The degree of hydrolysis of 2'-acetyl erythromycin to erythromycin was 23-43% higher in tonsil tissue than in circulation.

A simple and sensitive high-performance liquid chromatographic method was developed for the determination of 2'-acetyl erythromycin and erythromycin in human tonsil tissue. Methyl tert-butyl ether was used as the extraction solvent after alkalization of tissue homogenates. Separation was achieved on a reverse phase C-18 column. The mobile phase consisted of acetonitrile-methanol-tetrahydrofuran-sodium acetate buffer, pH 4.5. Eluted compounds were monitored by a coulometric detector in the oxidative screen mode. The quantitation limits of 2'-acetyl erythromycin and erythromycin were 0.20 and 0.30 mg/kg of tissue, respectively. The method was linear over the concentration range of 0.60-10.0 mg/kg of tissue for 2'-acetyl erythromycin and erythromycin.