Study of drug transport between the blood and lymph in the predominant direction.

Our method for evaluating the time course and intensity of antibiotics and other drugs transport in the predominant direction between the blood and lymph in humans promotes a more objective evaluation of drug circulation mechanisms, which is essential for determining the time of their repeated administration and route of administration. Calculation of the lymph/blood difference coefficient, based on parallel repeated measurements of the drug concentration in the lymph and blood, and of the lymph/blood coefficient provides complete data on the direction and time course of drug transport between the lymph and blood in the predominant direction.

Doxorubicin as an antioxidant: maintenance of myocardial levels of lycopene under doxorubicin treatment.

The mechanism of doxorubicin-induced cardiotoxicity remains controversial. Wistar rats (n=96) were randomly assigned to a control (C), lycopene (L), doxorubicin (D), or doxorubicin+lycopene (DL) group. The L and DL groups received lycopene (5 mg/kg body wt/day by gavage) for 7 weeks. The D and DL groups received doxorubicin (4 mg/kg body wt intraperitoneally) at 3, 4, 5, and 6 weeks and were killed at 7 weeks for analyses. Myocardial tissue lycopene levels and total antioxidant performance (TAP) were analyzed by HPLC and fluorometry, respectively. Lycopene metabolism was determined by incubating (2)H(10)-lycopene with intestinal mucosa postmitochondrial fraction and lipoxygenase and analyzed with HPLC and APCI mass spectroscopy. Myocardial tissue lycopene levels in DL and L were similar. TAP adjusted for tissue protein were higher in myocardium of D than those of C (P=0.002). Lycopene metabolism study identified a lower oxidative cleavage of lycopene in D as compared to those of C. Our results showed that lycopene was not depleted in myocardium of lycopene-supplemented rats treated with doxorubicin and that higher antioxidant capacity in myocardium and less oxidative cleavage of lycopene in intestinal mucosa of doxorubicin-treated rats suggest an antioxidant role of doxorubicin rather than acting as a prooxidant.

Systematic approach to understanding macrolide-ribosome interactions: NMR and modeling studies of oleandomycin and its derivatives.

The three-dimensional structures of oleandomycin (1) and its derivatives oleandomycin-9-oxime (2) and 10,11-anhydrooleandomycin (3) were determined in different solvents by the combined use of NMR and molecular modeling methods. The experimental NMR data were compared with the results of molecular modeling and known crystal structures of the related molecules. It was shown that the dominant conformation of the lactone ring is the folded-out conformation with some amounts of the folded-in one depending on the solvent and temperature, while desosamine and cladinose sugars adopt the usual chair conformations. Modeling calculations provided evidence for conformational changes in the upper lactone region as well. Saturation transfer difference (STD) NMR experiments have provided information on the binding epitopes of 1-3 in complexes with E. coli ribosomes. The obtained molecular surfaces in close contact with ribosomes were compared with recently available 3D structures of the related macrolide-ribosome complexes, and the observed differences were discussed. The knowledge gained from this study can serve as a platform for the design of novel macrolides with an improved biological profile.

Pharmacokinetics of oleandomycin in dogs after intravenous or oral administration alone and after pretreatment with metamizole or dexamethasone.

The pharmacokinetics of oleandomycin (OLD) after intravenous and oral administration, both alone and after intramuscular pretreatment with metamizole or dexamethasone, were studied in healthy dogs. After intravenous injection of OLD alone (10 mg/kg as bolus), the elimination half-life (t 1/2 beta, volume of distribution (Vd,area), body clearance (ClB) and area under the concentration time curve (AUC) were 1.60 h, 1.11 L/kg. 7.36 (ml/kg)/min and 21.66 microg h/ml, respectively. There were no statistically significant differences following pretreatment with metamizole or dexamethasone. After oral administration of OLD alone, the t 1/2 beta, maximum plasma concentrations (Cmax), time of Cmax (tmax), mean absorption time (MAT) and absolute bioavailability (Fabs) were 1.6 h, 5.34 microg/ml, 1.5 h, 1.34 h and 84.29%, respectively. Pretreatment with metamizole caused a significantly decreased value for Cmax (2.93 microg/ml) but the MAT value (2.23 h) was significantly increased. Statistically significant changes in the pharmacokinetic parameters of OLD following oral administration were also observed as a result of pretreatment with dexamethasone. The Cmax was increased (8.24 microg/ml) and the tmax (0.5 h) and MAT (0.45 h) were lower.

Identification of functional amino acids in the macrolide 2'-phosphotransferase II.

Macrolide 2'-phosphotransferase [MPH(2')] transfers the gamma phosphate of ATP to the 2'-OH group of macrolide antibiotics. The role of aspartic acids in the putative ATP-binding site of MPH(2')II was investigated through the substitution of alanine for aspartate by site-directed mutagenesis. D200A, D209A, D219A, and D231A mutant strains were unable to inactivate the substrate oleandomycin, while a D227A mutant retained 7% of the activity of the original enzyme.

New oleandomycin 9-oximes. Synthesis, characterization and biological activity.

A series of the novel oleandomycin 9-oximes has been prepared and characterized by spectroscopic data and X-ray analysis. The antibacterial in vitro activities of the oximes (6-10) were compared with that of oleandomycin (1). Among the novel derivatives the most active compound was 8(R)-methyloleandomycin-9-oxime (9) in contrast ot its 8(S)-isomer (10) which possessed only low potency. Some preliminary pharmacokinetic data of 9 confirmed its activity. Compound 9 has been advanced to further biological study.

[Kinetics of thermal inactivation of oleandomycin in aqueous and native alkaline solutions]. / Kinetika teplovoi inaktivatsii oleandomitsina v vodnykh i nativnykh shchelochnykh rastvorakh.

The process of oleandomycin inactivation in aqueous alkaline solutions with their heating was studied by using the microbiological method of the antibiotic content assay. The initial specific rate of inactivation of crystalline oleandomycin in buffer solutions and oleandomycin in the fermentation broth filtrate was evaluated. It was shown that the inactivation was retarded by the reaction products and the components of the fermentation broth filtrate. The production rate of oleandomycin anhydro derivatives amounting to 3-40 per cent of the total mass of the inactivation product was estimated by UV spectrophotometry.