Search

The pharmacokinetics of Josamycin was studied in 31 subjects (10 normals, 9 Gilbert's syndrome and 12 compensated liver cirrhosis) after the administration of Josamycin (1 g orally) and in 13 subjects (4 normals, 4 Gilbert's syndrome and 5 compensated liver cirrhosis) after 3-day Josamycin treatment (1 g orally every 12 hours). Josamycin pharmacokinetics was impaired in liver cirrhosis and, to a lesser extent, in Gilbert's syndrome. Moreover, in the three groups of individuals studied the drug accumulated after multiple dosing. These results suggest that a dosage adjustment of Josamycin is recommended when dealing with these patients.

The effects of a new macrolide antibiotic (Roxithromycin) and one of its major metabolite (RU 39001) on rat hepatic drug metabolizing enzymes were compared to those of erythromycin, erythralosamine and troleandomycin (TAO) both in vitro and in vivo. In contrast to erythromycin, erythralosamine and TAO, roxithromycin and its metabolite RU 39001 exhibit: (i) a very poor affinity for rat liver cytochrome P-450, (ii) an unability to be metabolized into a stable inhibitory metabolite-cytochrome P-450 complex and (iii) a decreased ability to induce liver cytochrome P-450 PCNE, an isozyme implicated in drug associations involving some macrolide antibiotics.

Esterases of intestinal mucosa and liver from human and rat were used to study the biotransformation of midecamycin derivatives. In the in vitro experiment with rat esterases, the 4"-acyl derivatives were more easily hydrolyzed than the 9-acyl derivatives. Among the 9-acyl esters, the highest hydrolytic activity was observed with butyrate. In the in vivo experiment, when the rats were administered with the derivatives of 4"-depropionylmidecamycin (M1) orally, comparatively more 9-acyl metabolites were excreted in the urine, but the amount of the 4"-acyl metabolites was very small. In the in vitro experiment with human esterases, the 9-acyl esters were hydrolyzed more easily than the 4"-acyl esters. Among the 9-acyl esters of M1, the highest hydrolytic activity was observed with butyrate. When the 9-acyl esters were administered to humans, the n-butyl ester was hydrolyzed faster than the acetyl ester. When the 9,4"-diacetyl ester was administered to humans, comparatively more 4"-acyl metabolites were excreted in the urine. These results suggest that the experiment with the use of these esterases is useful to estimate the biotransformation of midecamycin derivatives.

Tissue and plasma concentrations and the biological half-life of tylosin in avian species of a variety of body sizes and metabolic rates were studied. The species chosen were eastern bobwhite quail (Colinus virginianus virginianus), pigeons (Columba livia), greater sandhill cranes (Grus canadensis tabida), and emus (Dromaius novaehollandiae). In the 1st phase of this study, tylosin was administered IM to quail, pigeons, and emus at a dosage rate of 25 mg/kg of body weight and to cranes at a dosage rate of 15 mg/kg. The average peak plasma concentrations of tylosin in quail, pigeons, cranes, and emus were 4.31, 5.63, 3.62, and 3.26 microgram/ml, respectively. These peak concentrations occurred at 0.5 to 1.5 hours after administration. The biological half-life of tylosin averaged 1.2 hours in quail, pigeons, and cranes, and was 4.7 hours in emus. In the 2nd phase of this study, tylosin concentrations in the tissues of quail, pigeons, and cranes were markedly higher than were plasma concentrations at corresponding sampling times. Six hours after antibiotic administration, tissue concentrations of tylosin in all species remained within the minimum inhibitory concentration for most pathogenic organisms. Dosage regimens of 25 mg of tylosin/kg 4 times daily for quail and pigeons, 15 mg/kg 3 times daily for cranes, and 25 mg/kg 3 times daily for emus would be needed to establish and maintain therapeutic tissue concentrations.

Miocamycin (MOM) is a derivative of midecamycin and is metabolized into 4 main metabolites. In the present studies, we evaluated acute toxicity and estimated LD50 values of Mb6, one of the main metabolites of MOM, in male and female mice after single oral administration. Observations were continued for 1 week after treatment. The LD50 values were calculated according to Litchfield-Wilcoxon's method. It is concluded that LD50 values of Mb6 were 4,150 mg/kg (3,577.6 approximately 4,814.0 mg/kg) in male mice and 4,000 mg/kg (3,389.8 approximately 4,720.0 mg/kg) in female mice, respectively.

Carbomycin A (deltamycin A4) was deepoxidized to carbomycin A P1 by Streptomyces halstedii subsp. deltae (a deltamycins producer), favorably under anaerobic conditions. Carbomycin A P1 was spontaneously converted to geometric isomers designated carbomycins A P2 and A P3. This type of deepoxidation and subsequent isomerization was not limited to carbomycin A, but generally occurrable in other 16-membered epoxyenone macrolide compounds. Many bacteria and actinomycetes were also found to have an ability to deepoxidize deltamycins reductively. The chemical structures of carbomycins A P1, A P2 and A P3 were elucidated as shown in Fig. 3.

Ponsinomycin is a new macrolide. Following oral administration, ponsinomycin is totally metabolized, even before reaching blood circulation. Metabolite Mb12 is the first compound on the main metabolic route, which can be assayed. The influence of food on ponsinomycin bioavailability has therefore been estimated from measurements of Mb12 plasma levels. Twelve young healthy volunteers received 800 mg of ponsinomycin as a syrup on two separate occasions, 2 hours before and during a standard meal. The Mb12 metabolite was assayed in plasma by High Pressure Liquid Chromatography (HPLC). Plasma peak concentrations and areas under curves were not significantly different but time to peak was significantly shorter when ponsinomycin was administered during meal. The results suggest that ponsinomycin absorption is faster when administered with food but quantitatively unchanged.

Miocamycin (MOM) is a derivative of midecamycin and is metabolized into 4 main metabolites of Mb1, Mb2, Mb6 and Mb12. It is also known that LD50 values of Mb6 were 4,150 mg/kg in male mice and 4,000 mg/kg in female mice but LD0 values in male and female rats were estimated more than 5,000 mg/kg. The object of this study was to examine subacute toxicological effects in male and female rats after repeated oral administration of Mb6 for 5 weeks at a daily dosage of 125, 250, 500 and 1,000 mg/kg. It is concluded that no manifest toxicity was observed in this study with Mb6 in male and female rats after oral administration at dosage levels of 125, 250, 500 and 1,000 mg/kg for 5 weeks.

After a consecutive oral administration of 200 mg/kg/day of 14C-rokitamycin (TMS-19-Q) daily for 28 days to male rats, the accumulation of radioactivity in tissues and its disappearance after the cessation of the administration was studied. Blood concentrations at peak times and 24 hours after each administration were determined daily. Both values increased gradually until the 14th day and thereafter remained roughly constant. The extent of elimination of radioactivity from the blood was practically not affected by the consecutive administration. Affinities of radioactivity to the liver, kidney, spleen, adrenal, pituitary gland, preputial gland, thyroid, intraorbital lacrimal gland and bone marrow were comparatively higher than those to other tissues. Tissue concentrations in the above mentioned tissues at the 1st day after the completion of consecutive administrations for 14 and 28 days were 2.6-6.1 and 3.2-6.8 times higher, respectively, than those at the 1st day after a single administration. The elimination of radioactivity from the tissue after the consecutive administration for 28 days was slightly slower than that after a single administration. In the consecutive daily administration for 28 days, the metabolic fate of radioactivity reached a steady state after 14 days of consecutive daily administration. Hence, the accumulation of the radioactivity did not particularly occurred. During the consecutive administration, recoveries of radioactivity in the urine and feces were almost at a constant rates, with 8.0 and 93.8% of the total radioactivity given excreted in the urine and feces, respectively, within 10 days after the last administration.

Eleven 4''-O-acyltylosin derivatives were synthesized and subjected to a two-step screening system consisting of antimicrobial activity and esterase stability assays. The new derivatives were all active against macrolide-resistant Staphylococci and mycoplasmas, but only 4''-O-(4-methoxy)phenylacetyltylosin and 4''-O-(4-acetyl)phenylacetyltylosin showed better resistance to mouse liver esterase than 4''-O-phenylacetyltylosin (reference compound C).

Turimycin H0 was isolated from the bile of rats as main metabolite after i.v. administration of turimycin H. It was also obtained by incubation of turimycin H with liver homogenates of dogs and rats. Degradation of turimycin H by liver homogenate of pigs was found to be relatively slow. Turimycin H0 was identified as 4"-deacylturimycin H by MS.

Miocamycin (MOM) is a derivative of midecamycin, a macrolide antibiotic and is metabolized into 4 main metabolites of Mb1, Mb2, Mb6 and Mb12. In the previous study, LD0 values of Mb1 were estimated more than 5,000 mg/kg in male and female rats as Mb1 did not exhibited any lethal toxicity even at the maximum physically applicable dose of 5,000 mg/kg. The object of this study was to examine subacute toxicity in male and female rats after repeated p.o. administration of Mb1 for 5 weeks at a daily dosage of 125, 250, 500 and 1,000 mg/kg. It is concluded that no manifest toxicity was observed in this subacute toxicity study on Mb1 in rats.

The pharmacokinetics of 3 antibiotics--chloramphenicol, lincomycin, and tylosin--were determined in newborn calves. The kinetic determinations, using 2-compartment open models, were made at increasing ages from 1 day to 42 days and compared with those made from 9-month-old calves. Although all 3 antibiotics require a degree of hepatic metabolism, there were marked differences in the development of elimination processes for the individual drugs. Elimination of tylosin, which was slow in the calves at birth, increased rapidly and was equal to that in older calves by the end of 1 week. Lincomycin elimination was not markedly reduced in calves at birth. Chloramphenicol elimination was slow in calves at birth and only by 4 to 6 weeks attained the rate found in older calves. Dosage adjustments would not be required for the antibiotics tylosin or lincomycin when given to newborn calves, but may be necessary for chloramphenicol given to calves before they are 4 to 6 weeks old.

14C-Rokitamycin (RKM) at the dose of 200 mg/kg was administered orally to fasted infant rats to study the absorption, distribution, metabolism and excretion in infant animals. The mean blood level of 14C-RKM reached its peak of 20.25 micrograms/ml in 30 minutes. The mean area under the curve was 93.23 micrograms.hr/ml. In vivo plasma protein binding rates of 14C-RKM were about 30% in both infant and adult rats. 14C-RKM was distributed at high concentrations into liver, kidney, lung, spleen, pancreas, bone marrow, submaxillary gland and some other tissues. Major metabolites detected in plasma, urine and bile were 10"-OH-RKM, leucomycin A7, leucomycin V and 14-OH-leucomycin V. In excretion studies, about 97% of the administered radioactivity was recovered in urine and feces within 144 hours. After intraduodenal administration to rats with cannulated bile ducts, 7.42% and 25.66% of the radioactivity were excreted within 24 hours in the urine and bile, respectively.

Streptomyces sp. strain No. K-245 was found to transform maridomycin III into four derivatives (A1, A2, A3 and A4) in addition to the transformation products reported previously. Isolation of the main product A1 was carried out by column chromatography on silica gel developed with CHCl3-MeOH (19:1). From the partial investigation of the structure of A1, it proved to have a C-18-aldehyde group and C 4''-propionyl group but no antimicrobial activity. The relationships between A group's derivatives and known derivatives of maridomycin III are also discussed.

Determination of the distribution coefficients in vitro demonstrates that josamycin (Wilprafen) is at least 15 times more lipophilic than erythromycin. On the other hand the distribution coefficients of penicillin G and of amoxicillin be in the hydrophilic range. The serum protein binding of josamycin is 15%, which is markedly less than with the other macrolides. These in vitro experiments show that small structural differences can alter the physicochemical and biological behaviour of an antibiotic, even when the molecules are closely related. A cross-over experiment with 12 volunteers and multiple application of 1 g of josamycin base or 1.175 g of erythromycin ethyl succinate showed that both macrolides are rapidly absorbed and reach their maximum within the first hour. In 21 patients the concentration of josamycin in lung tissue was 2 to 3 times that in the blood. The highest concentration of josamycin reached was 3.68 micrograms/g lung tissue (mean of 12 patients) and this was found for the group of patients from whom the tissue samples had been taken 2-3 h after the last administration of the drug. Lower mean concentrations of erythromycin were found in the serum and lung tissue of a similar group of 31 patients. The results indicate that the new macrolide antibiotic josamycin accumulates well in lung tissue and that the concentrations necessary for the treatment of infections (minimal inhibitory concentrations [MIC]) are rapidly reached also in the tissue.

Fourty patients undergoing tonsillectomy for recurrent tonsillitis were administered penicillin V, amoxicillin, cefaclor or josamycin. Antibiotic concentrations in serum and tonsillar tissues were determined by microbiological assay. Cefaclor demonstrated a superior diffusion than penicillin V and amoxicillin, but nevertheless inferior to that of josamycin.

Miocamycin (MOM) is a derivative of midecamycin and is metabolized into 4 main metabolites of Mb1, Mb2, Mb6 and Mb12. In the previous studies, we estimated LD50 values of Mb6 in male and female mice after single oral administration. The LD50 values were 4,150 mg/kg in male mice and 4,000 mg/kg in female mice, respectively. In the present studies, we evaluated acute toxicity and estimated LD50 values of Mb6 in male and female rats after single oral administration. Observations were continued for 1 week after treatment. It is concluded that LD0 values of Mb6 in male and female rats, were estimated more than 5,000 mg/kg as Mb6 did not exhibit any manifest acute toxicity even at the maximum physically applicable dose of 5,000 mg/kg.

The synergistic effect of type A (virginiamycin M (VM)) and type B (virginiamycin S (VS)) synergimycins and their antagonistic effect against erythromycin (a 14-membered macrolide) for binding to the large ribosomal subunit (50 S) have been related. This investigation has now been extended to 16-membered macrolides (leucomycin A3 and spiramycin) and to lincosamides (lincomycin). A dissociation of VS-ribosome complexes was induced as well by 16-membered macrolides as by lincosamides. The observed dissociation rate constant of VS-ribosome complexes was identified with the kappa-vs in the case of 16-membered macrolides, but linearly related to lincomycin concentration, suggesting a direct binding of the latter antibiotic to VS-ribosome complexes and the triggering of a conformational change of particles entailing VS release. Two different mechanisms were also involved in the VM-promoted reassociation to ribosomes of VS previously displaced by either macrolides or lincosamides. By binding to lincosamide-ribosome complexes, VM induced a conformational change of ribosomes resulting in higher affinity for VS and lower affinity for lincosamides. On the contrary, an incompatibility for a simultaneous binding of VM and 16-membered macrolides to ribosomes was observed. These results have been interpreted by postulating specific (nonoverlapping) and aspecific (overlapping) antibiotic binding sites at the peptidyltransferase domain. All the kinetic constants of five antibiotic families (type A and B synergimycins, 14- and 16-membered macrolides, and lincosamides) and a topological model of peptidyltransferase are presently available.

Knowledge of the disposition of macrolides in a single animal species has been insufficient for the prediction of the pharmacokinetics of macrolides in humans. To better understand the species differences in the pharmacokinetics of macrolide antibiotics, the disposition of erythromycin, oleandomycin, and tylosin in several mammalian species was examined. Generally, the serum concentration versus time profiles of these drugs after intravenous administration were described by two-compartment kinetic models and were similar within each species. These drugs were rapidly cleared, resulting in terminal half-lives of less than 2 h. Comparison of their pharmacokinetics showed greater variation in antibiotic disposition among animal species than noted for the differences within a species. When the pharmacokinetic data was fitted to an allometric model, the logarithms of volume of distribution, clearance, and half-life were linearly related to the logarithms of body weight. From these relationships, the human pharmacokinetics of erythromycin and oleandomycin were extrapolated and found to approximate observed human pharmacokinetics.

Abosrption, distribution and excretion of 14C-josamycin (JM) and 14C-josamycin propionate (JM-P) were studied in rats by measuring both antibacterial activity and radioactivity. 1. In antibacterial activity, plasma and tissue concentrations of JM-P showed a similar tendency to those of JM. Those concentrations of JM reached a peak at 1 hour after administration with a subsequent rapid decrease, while the peak level of JM-P appeared 2 approximately 4 hours after administration and then fell down very slowly. 2. In radioactivity, oral administration of JM-P rapidly produced a very high plasma and tissue concentrations which were in lung, liver, kidney and spleen more than twice those of JM. These results showed that when given orally, JM-P is well absorbed with distributions at high concentrations especially in lung, liver, and kidney and spleen. 3. The ratios of bioactivity/radioactivity in JM administration were the highest in lung and the lowest in liver at 1 hour after. But those of JM-P were generally much lower than those of JM because of higher distribution of JM-P radioactivity into tissues. 4. Four days after oral administration of JM and JM-P, 23.1% and 21.8% of the given radioactivity were recovered respectively from urine. However, the antibacterial activities recovered were 0.40% for JM and 0.65% for JM-P. 5. Biliary recoveries of JM and JM-P were 17.2% and 12.1% of administered radioactivity 2 days after oral administration. On the other hand, 0.47% of JM and 0.17% of JM-P were excreted into bile as antibacterial activity. These results showed that JM and JM-P were excreted into rat urine and bile as some metabolites with less biological activity. 6. The amounts of JM and JM-P recovered from feces were 75.7% and 60.2%, respectively, of the orally given radioactivity. The amount of radioactivity recovered from expiration air was about 1% of either orally given JM or JM-P.

Due to their high intracellular uptake, macrolides may interfere with phagocytes antibacterial system. We have studied the interaction of josamycin with bactericidal activity of human neutrophils (PMNs) or whole blood, in vitro. PMNs preincubated with josamycin (100-0.1 mg/l) display an increased phagocytic ability for K. pneumoniae, independently of the concentrations of josamycin; this effect appears to correlate with the recruitment of an additional population of phagocytizing PMNs without alteration of the mean number of PMN-associated bacteria, whatever the experimental conditions (adherent or non adherent PMNs). PMNs bactericidal function is also enhanced in the presence of josamycin in a dose-dependent manner (mean increase 60 to 370% for josamycin 0.1 to 10 mg/l). Bactericidal activity of whole human blood for P. aeruginosa (a strain resistant to the lytic effect of serum) is increased with a mean survival (CFUt min/CFU 0 min) of 24 and 71% at 60 and 120 min respectively, in the presence of josamycin 10 mg/l, and 42 and 128% in the presence of josamycin 1 mg/l, compared to the survival of the control, 68 and 166%. PMNs functions are not altered by josamycin with the exception of an enhancement of the oxidative burst induced by formylmethionyl-leucyl-phenylalanine, a synthetic compound similar to bacterial derivatives. In conclusion, we have shown a synergic interaction between phagocytes and josamycin for the killing of bacteria resistant to this antibiotic (MiC greater than 128 mg/l). This could be due either to an alteration of some PMN membrane receptors or to alterations of bacteria which render them more sensitive to natural bactericidal mechanisms and/or more able to activate these mechanisms.

The affinity of ribosomes for VS (virginiamycin S, a type B synergimycin) is known to be increased by VM (virginiamycin M, a type A synergimycin). Erythromycin, a macrolide, displaces ribosome-bound VS in the absence of VM, but is ineffective in its presence. In the present work, the ability of spiramycin and tylosin (macrolide subgroups) derivatives to displace ribosome-bound VS, in the presence and in the absence of VM, has been explored. All macrolides with in-vitro activity displaced ribosome-bound VS: the displacement curves produced by tylosin and spiramycin derivatives virtually overlapped. When VM was added to these systems, displaced VS became readily attached to ribosomes in the case of erythromycin, did not bind appreciably within 20 min incubation in the presence of tylosin, and underwent a slow binding in the case of an N-substituted tylosin. The 16-membered macrolides (leucomycin, spiramycin and tylosin subgroups) can therefore be distinguished from the 14-membered macrolides (erythromycin subgroup) by the antagonistic effect displayed toward VM.

The degree of penetration of roxithromycin in human macrophages was evaluated and compared with that of erythromycin. The results indicated that both macrolides at concentrations of 2, 10 and 20 micrograms/ml were concentrated by macrophages, even if roxithromycin was consistently and significantly more accumulated than erythromycin. Comparison of the degree of penetration of the two drugs into dead, resident and stimulated phagocytes indicated that the process of transfer through the macrophage wall was of an active nature, related to the metabolic state of the cells. Analysis of the binding of the two macrolides to intracellular proteins showed that more binding sites were available for erythromycin than for roxithromycin.

Two macrolide antibiotics, josamycin and erythromycin stearate, were administered orally to healthy, adult male volunteers for a comparative study of their pharmacological properties. In comparable doses, josamycin and erythromycin produced similar plasma concentrations, with similar half-lives and elimination constants. An initial loading dose of 1.5 g of josamycin produced greater peak concentrations of antibiotic throughout a 10-day period with a regimen of every 6 h. In addition, josamycin tended to reach higher peak and trough concentrations after regimens of every 6 or 8 h were maintained for 2 days. Josamycin penetrated into saliva, sweat, and tears, and it was better tolerated in fasting subjects than was erythromycin stearate.

To gain a better understanding of the antibacterial and antiprotozoal activity of spiramycin as well as the characteristic conditions of cellular defence, we studied its accumulation and intracellular localization in cultured macrophages. Within two hours spiramycin in its active form is accumulated intracellularly by macrophages to a concentration 10 to 20 times that found in the extracellular medium; it is released slowly by the cells when they are incubated in antibiotic-free medium. After differential or isopycnic centrifugation, a bimodal localization of spiramycin was found; one part could be associated with the soluble cytosolic fraction and another with organelles sedimenting at a density of 1.17 g/ml, which represent part of the lysosomal population and perhaps the phagosomes.

Phosphate limitation induces the turimycin biosynthesis as well as the cAMP phosphodiesterase and phosphatase. The results are discussed in connection with the observation of general high activities of dephosphorylating enzymes and low concentrations of phosphorylated intermediates under conditions of phosphate limitation and secondary product biosynthesis, respectively.

Miocamycin (MOM) is a derivative of midecamycin and is metabolized into 4 main metabolites. At previous study, LD0 values of Mb1 were estimated more than 5,000 mg/kg in male and female mice. The object of this study was to evaluate acute toxicity in male and female mice after single oral administration of Mb2, a metabolite of MOM, at a dose level of 5,000 mg/kg as the maximum physically applicable dose. It is concluded that LD0 values of Mb2 were estimated more than 5,000 mg/kg.

CC-1065, a novel antibiotic produced by Streptomyces zelensis, was active against several experimental tumors in vivo and a broad spectrum of human tumor cells in vitro. This report describes its biological and biochemical effects of L1210 leukemia cells. CC-1065 is one of the most cytotoxic agents known. The concentrations required for a 50 and 90% inhibition of cell growth are 0.02 and 0.05 ng/ml, respectively. It is about 400 times more cytotoxic than was Adriamycin. The action of CC-1065 is rapid and is dose and time dependent. CC-1065 inhibits DNA synthesis much more than it inhibits RNA and protein synthesis. The concentrations required for a 50% inhibition of DNA synthesis and RNA synthesis are 4 to 6 and 45 to 60 ng/ml, respectively. Although the drug inhibition of DNA synthesis cannot completely account for its cytotoxic effects on L1210 cells, these results, along with those generated by other investigators, suggest that the inhibition of DNA synthesis represents a major mode of action of CC-1065. CC-1065 inhibited both thymidine kinase and DNA polymerase alpha activities, but the effect on highly purified DNA polymerase alpha was more pronounced. At 1 microgram/ml, CC-1065 inhibited more than 70% of the enzyme activity. In order to elucidate the mechanism of inhibition of DNA polymerase alpha, the interaction between CC-1065 and DNA was investigated. The studies with thermal melting of DNA and difference circular dichroism measurement indicate that CC-1065 is one of the strongest DNA-binding agents. It induced an increase in thermal melting temperature of calf thymus DNA by at least 31 degrees. The circular dichroism studies also reveal that CC-1065 binds only to double-stranded DNA but not to heat-denatured DNA or yeast RNA. These observations were supported by those obtained with two other experimental approaches. CC-1065 also appeared to interact with proteins, but the interaction was weak and reversible.