Kinetics of macrolide action: the josamycin and erythromycin cases.

Members of the macrolide class of antibiotics inhibit peptide elongation on the ribosome by binding close to the peptidyltransferase center and blocking the peptide exit tunnel in the large ribosomal subunit. We have studied the modes of action of the macrolides josamycin, with a 16-membered lactone ring, and erythromycin, with a 14-membered lactone ring, in a cell-free mRNA translation system with pure components from Escherichia coli. We have found that the average lifetime on the ribosome is 3 h for josamycin and less than 2 min for erythromycin and that the dissociation constants for josamycin and erythromycin binding to the ribosome are 5.5 and 11 nM, respectively. Josamycin slows down formation of the first peptide bond of a nascent peptide in an amino acid-dependent way and completely inhibits formation of the second or third peptide bond, depending on peptide sequence. Erythromycin allows formation of longer peptide chains before the onset of inhibition. Both drugs stimulate the rate constants for drop-off of peptidyl-tRNA from the ribosome. In the josamycin case, drop-off is much faster than drug dissociation, whereas these rate constants are comparable in the erythromycin case. Therefore, at a saturating drug concentration, synthesis of full-length proteins is completely shut down by josamycin but not by erythromycin. It is likely that the bacterio-toxic effects of the drugs are caused by a combination of inhibition of protein elongation, on the one hand, and depletion of the intracellular pools of aminoacyl-tRNAs available for protein synthesis by drop-off and incomplete peptidyl-tRNA hydrolase activity, on the other hand.

Comparative bioavailability of josamycin, a macrolide antibiotic, from a tablet and solution and the influence of dissolution on in vivo release.

The bioavailability of josamycin from a tablet formulation (2 x Josacine 500 mg tablets) was investigated and compared with the bioavailability of a solution (containing 1 g drug and buffered at pH 4.0) following administration to six healthy human volunteers. Bioavailability profiles for the solution indicated that the drug was inherently rapidly absorbed with a mean Cmax of 1.64 +/- 0.67 mg L-1 attained at a mean tmax of 0.39 +/- 0.08 h. The AUC0-last was 1.510 +/- 0.687 mg h L-1. Bioavailability was significantly lower from the tablets than from the solution. Highly variable serum concentration-time profiles were obtained from the tablets and Cmax values ranged from 0.05 to 0.71 mg L-1 with a tmax range of 0.33-2.0 h. AUC0-last values ranged from 0.03 to 0.95 mg h L-1. Dissolution of josamycin from the tablets was generally unaffected at low pH (pH 1.2-5.0), but, rather, limited predominantly by tablet disintegration. However, dissolution was increasingly limited as the pH increased from 5.0 to 9.0. Besides poor disintegration, the particularly low intrinsic dissolution rate and solubility of josamycin at these pH values is likely to further reduce the dissolution rate. Comparison of the solution and tablet serum concentration-time profiles suggests that the absorption of josamycin from the tablets was dissolution rate limited. This is supported by the in vitro dissolution-pH topogram, which suggests that dissolution will be particularly rate limiting if dissolution of whole or parts of tablets occurs in gastro-intestinal fluid above pH 5.0.

[A comparative study on the pharmacokinetics of josamycin in Chinese Han, Uighur and Kazak healthy volunteers].

Six Han, 6 Uighur and 6 Kazak healthy volunteers took orally a single dose of 1000 mg josamycin tablets. The concentrations of the drug in serum were detected with bioassay method. The results showed that the pharmacokinetic courses were very similar among these three ethnic groups and fitted to a one-compartment open model. The results in these three groups showed no significant difference.

Multiple dose bioequivalence study with josamycin propionate, a drug with highly variable kinetics, in healthy volunteers.

Josamycin is a macrolide antibiotic with considerable intra- and interindividual variability in kinetics. In the present study bioequivalence of an intact and dispersed josamycin Solutab tablet, containing 1,000 mg of josamycin in the form of josamycin propionate ester, was tested versus a Josacine 1,000 mg reference sachet. The design of this bioequivalence study was adapted to the drug's pharmacokinetic variability, comprising testing in steady-state, testing the reference in replicate, and maintaining a widened bioequivalence margin. The study was performed in a group of 24 male and 12 female healthy subjects, according to a 3-treatment 4-period crossover design. Blood sampling for establishing josamycin propionate and josamycin base serum level profiles were collected during the 12 h dosing interval on day 4. Steady-state serum levels were reached on day 4. With the reference sachet mean peak levels of 1.02 micrograms/ml and 0.36 microgram/ml were observed for parent drug and metabolite, respectively, reached at peak times of 1.5 h and 1.8 h. Comparable profiles were observed with the intact and dispersed Solutab tablets, both tending towards higher serum levels than the sachet. In terms of josamycin propionate levels as well as josamycin base levels, the intact and dispersed Solutab tablet was bioequivalent with the referent sachet within the preset 0.70-1.43 margins. Variability in josamycin kinetics proved to be substantial, maximum differences in peak levels and AUC values being about 10-fold between individuals, and 3-fold within individuals. Retrospectively, the multiple dosing regimen appeared not to result in a clear reduction of intrasubject variability.

Pharmacokinetic and bacteriological study of cefadroxil-salicylate and josamycin-salicylate drug regimens.

Eye, nose, throat and bronchopulmonary infections are frequently associated with inflammatory symptoms. This often leads the clinician to prescribe a combination of an anti-inflammatory and an antibiotic. Cefadroxil and josamycin are among the antibiotics most frequently used in these infections, and they are often combined with acetylsalicylic acid in various pharmaceutical formulations. The study of possible pharmacokinetic and bacteriological interactions was performed in healthy volunteers who received in a crossover protocol each of the two antibiotics, either alone or combined with acetylsalicylic acid or lysine acetylsalicylate. No marked pharmacokinetic interaction was noted except an increase in the AUC for plasma concentrations of cefadroxil when combined with a salicylate. A greater uniformity of kinetic profiles was seen with cefadroxil than with josamycin. Lastly, with the exception of one strain, the salicylates did not alter the antibacterial activity of cefadroxil.

Josamycin concentrations in radicular cysts following a single oral administration.

1. Josamycin concentrations in cyst wall (wall) and cyst fluid (fluid) of radicular cyst and serum following a single oral administration of josamycin (600 mg) were assayed by a paper disk method. 2. The mean peak josamycin concentrations in wall, fluid and serum occurred at 1.5, 2 and 1.5 hr, respectively, and were 1.33 micrograms/g, 0.53 and 0.74 micrograms/ml, respectively. 3. The mean concentration ratios of wall/serum, fluid/serum and fluid/wall at the peak times (1.5, 2 and 2 hr) were 1.80, 0.64 and 0.42, respectively. 4. Josamycin concentrations in wall and fluid at the peak time exceeded MIC for 80% for clinically isolated strains of alpha-hemolytic Streptococci.

Sensitive determination of josamycin and rokitamycin in plasma by high-performance liquid chromatography with fluorescence detection.

Rokitamycin and josamycin were successfully derivatized with dansylhydrazine in 20 min at 60 degrees C. Rokitamycin and josamycin levels were determined in plasma after ion-pair extraction into hexane-isoamyl alcohol with lauryl sulphate and precolumn derivatization. Resolution was obtained by liquid chromatography with fluorescence detection (352/537 nm) in 12 min. The limit of detection was 20 ng/ml macrolide starting from 1 ml of plasma, and linearity was demonstrated between 50 and 400 ng/ml. Inter-run coefficients of variation were 10.2% at 100 ng/ml and 9.1% at 300 ng/ml. The system was reliably used for pharmacokinetic studies in plasma.

Pharmacokinetics and tissue residues of josamycin in fowls.

Josamycin is a macrolide antibiotic which is produced by fermentation of cultures of Streptomyces narbonensis. It was once administrated (18 mg/kg b. wt.) in fowls via intravenous, oral and intramuscular routes for determination of blood concentration, kinetic behaviour and bioavailability. Following a single intravenous injection, the blood concentration-time-curve indicated a two compartments open model with an elimination half life value (t1/2 beta) of 1.83 +/- 0.06 hours. Both oral and intramuscular routes showed higher values, i.e. 2.33 +/- 0.13 and 2.85 +/- 0.17 hours. The lower apparent volume of distribution of Josamycin in fowls than one liter/kg elucidate higher distribution in blood than in tissues. Systemic bioavailability after both oral and intramuscular administration, i.e. 33.88 +/- 2.4 and 27.28 +/- 1.46% respectively, showed lower absorption from site of i.m. application. Josamycin was administered (18 mg/kg b. wt.) intramuscularly and orally once daily for 5 consecutive days. The drug peaked in serum 1 hour (intramuscular) and 2 hours (orally) after each dose. The recorded results revealed that serum level of Josamycin was higher after oral application (29.98 +/- 1.92 micrograms/ml) than after i.m. application. The drug persisted in the lung tissues and fat for 72 hours after administration and disappeared from all body tissues 96 hours after the last dose of repeated administration.

Residues of macrolide antibiotics in eggs following medication of laying hens.

1. The elimination kinetics of four macrolide antibiotics (tylosin, erythromycin, spiramycin and josamycin) in eggs were determined separately for albumen and yolk after oral administration through either drinking water or diet or after intramuscular injection. 2. Residues were assayed by a plate diffusion technique in cylinders with Micrococcus luteus as the test-organism. 3. Drug excretion was usually over a longer time in the yolk. Spiramycin was the most highly excreted in the egg whereas seven to eight times less tylosin and erythromycin was transferred. The conditions for the use of macrolide antibiotics in laying hens are discussed.

Comparative efficacy and tolerance of erythromycin and josamycin in the prevention of bacteraemia following dental extraction.

The tolerance and pharmacokinetics of erythromycin stearate and josamycin base were compared in healthy dental students. The efficacy and tolerance of the two antibiotics were compared in the prevention of bacteraemia following dental extraction. Erythromycin achieved higher serum levels at the time of extraction in dental patients than did josamycin. Erythromycin was rapidly and better absorbed than josamycin in the student volunteers, but josamycin caused less gastrointestinal side effects than erythromycin. Both antibiotics were only marginally more effective than placebo in preventing bacteraemia following dental extraction.

Chemical modification of erythromycins. III. In vitro and in vivo antibacterial activities of new semisynthetic 6-O-methylerythromycins A, TE-031 (clarithromycin) and TE-032.

The in vitro and in vivo antibacterial activities of 6-O-methylerythromycin A (TE-031, A-56268, or clarithromycin) and 6,11-di-O-methylerythromycin A (TE-032) have been compared with those of erythromycin A (EM) and josamycin (JM). TE-031 and TE-032, having the same antibacterial spectra as EM, are active against aerobic Gram-positive bacteria, some Gram-negative bacteria, anaerobic bacteria, L-form bacteria and Mycoplasma pneumoniae. The activity of TE-031 against clinical isolates is equal to or two times more potent than that of EM, whereas TE-032 is slightly less active than EM. The activities of TE-031 and TE-032 are pH dependent (more active at pH 8 than at 5) and are increased by adding serum to medium. TE-031 and TE-032 show dose-related bactericidal activities against Haemophilus influenzae. The therapeutic efficacies of TE-031 and TE-032 against systemic and subcutaneous infections provoked by Gram-positive bacteria in mice are 4- to 35-fold superior to those of EM and JM. TE-031 and TE-032 have demonstrated higher and longer-lasting plasma levels than EM when administered orally to mice, rats or dogs.

Josamycin concentrations in human dental granuloma after a single oral administration of josamycin.

1. Josamycin concentrations in human serum and dental granuloma after a single oral administration of josamycin (600 mg) were assayed by an agar diffusion (paper disc) method. 2. The mean peak josamycin concentrations in serum and dental granuloma occurred at an identical time, approximately 90 min, and were 0.88 micrograms/ml and 1.61 micrograms/g, respectively. 3. The mean concentration ratio of dental granuloma to serum at the peak time was 2.24. 4. Josamycin concentration in dental granuloma at the peak time exceeded MIC80 for clinically isolated strains of Streptococcus group A, Peptostreptococcus spp., and Bacteroides spp.