The awareness of drug interaction is of obvious interest to health care professionals. The present work comprises of interaction studies of most commonly used macrolides i.e., erythromycin, clarithromycin and roxithromycin with various essential and trace elements, and H-2receptor antagonist such as cimetidine, ranitidine, famotidine and nizatidine.
These macrolide antibiotics are active agairst a wide range of Gram positive and Gram negative bacteria and other infectious agents, including penicillinase producing Staphylococci, and Staphylococci, and species [22, 25]. Erythromycin is a broad spectrum antibiotic with activity against Chlamydia trachomatis, Mycoplasma, pneumoniae, Ureaplasma, Urealyticllm, Spirochetes, Treponema pallidllm and Borrelia species . Clarithromycin is a derivative of erythromycin, which also shows in vitro activity against many Gram-positive and Gram-negative aerobic and anaerobic organisms. The minimum inhibitory concentration (MIC) is generally two to four fold lower than that of erythromycin against Gram-positive bacteria, such as methicillin-sensitive Staphylococcus aureus and most Streptococcus species. Clarithromycin is bactericidal against Staphylococcus pyogenes, Staphylococcus pneumoniae and effective against Mycobacterium avium complex in human macrophages. Clarithromycin has greater in vitro activity than erythromycin against Legionella pnellmophi/a, Moraxel/a (Branhamella) catarrhalis, Chlamydia trachomatis, Ureaplasma urealyticum, Mycoplasma pneumoniae and Chlamydia trachomatis [378-379]. Roxithromycin is also a derivative of erythromycin, which shows similar range of activity to the later but is much more active in vivo . Since the presence of complexing ligand may affect the bioavailability of metal in the blood or tissues therefore, the probable interaction of these macrolide were studied with magnesium, calcium, chromium, manganese, iron, cobalt, nickel, copper, zinc and cadmium metal salts. in vitro. All the reaction conditions were simulated to body environments and beyond to perform extended temperature studies.
The effect of pH on drug-metal complexation was ~so studied. These studies were carried out in buffers ranging from pH 1-3, in variable ratios of drug: metal, clarithromycin and roxithromycin being insoluble in pH 4-9. The interactions of all macrolide;; with metals resulted in decrease in absorbtion of drug in presence of all metals and pH studied. The stability of these complexes were determined in order to evaluate their possible in vivo implications. In order to investigate the number of metal ions involved in complexation with each macrolide, method of continuous variation was adopted.
Synthesis of metal complexes of erythromycin, clarithromycin and roxithromycin. were carried out with the salts of above stated elements. The structures of these complexes were elucidated by exploiting various analytical techniques such as 'H-NMR, infrared, ultraviolet studies, conductance measurement, the metals incorporated in the complexes analysed by atomic absorbtion and finally x-ray diffraction analysis of magnesium an:! manganese complexes of clarithromycin has proved that the drug molecule serves as a monodentate ligand coordinating through tertiary nitrogen at desosamine.
Drug interaction studies of these macrolides has also been carried out with H,-receptor antagonists. Macrolide and H2-receptor antagonists are commonly coadministered in patients complaining of GI irritation, acidity or ulcerative colitis. The behavior of erythromycin, clarithromycin and roxithromycin in presence of H2-receptor antagonists such as cimetidine, ranitidine, famotidine and nizatidine were studied in simulated gastric juice (pH I), buffers of pH 4,7.4 and 9 at 37, 48 and 60°C by using standard dissolution test apparatus. The percentage of each drug available at various time intervals was quantitated by measuring the absorbance at the maxima of each drug and using simultaneous equation. It has been established that macrolides also interact \\ith these H,-receptor antagonists.
To evaluate the changes in microbiological activity of these drugs after complexation with various essential and trace elements, antibacterial studies of these complexes were carried out against both Gram positive and Gram negative organisms such as Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, Salmonella typhi, Proteus vulgaris, Shigella dysentery, Kelebcilla pneumoni and Staphylococcus epidermidis.
The changes in MIC of the complexes were compared with the parent drugs by measuring the zone of inhibition of these complexes. For MIC observation, agar dilution method was employed and zone series were determined by disk diffusion method. Our investigations divulge that erythromycin and clarithromycin metal complexes result in synergistic effects whereas roxithromycin metal complexes result in antagonistic effect.