The research work comprises of drug interaction studies of glibenclamide and glicIazide with antacids, H2-receptor antagonists and essential and trace elements.GlicIazide and glibenclamide are sulphonylurea derivatives, used in non-insulin dependent diabetes mellitus (NIDDM) and belong to second generation, which have higher potency than first generation drugs. They stimulate insulin release, possibly via interaction with receptors in the pancreatic β cells. They are readily absorbed in the gastrointestinal tract and extensively bound to plasma protein. The effect of several of these drugs may be increased if they are ingested half an hour before mea!(s). Short acting sulfonylureas may be safer than long acting ones, which seem more likely to cause long lasting and fatal hypoglycemia, at least in elderly patients.
Antacids and H2-receptor antagonists are commonly used in patients complaining of GI irritations. The antacids used in these studies are aluminum hydroxide, aluminum trisilicate, magnesium oxide, magnesium trisilicate, sodium bicarbonate, calcium carbonate, magaldrate and simethicone (2,4-dimethoxypolysiloxane). In vitro availability studies of gliclazide and glibenclamide were carried out in presence of these antacids in simulated gastric juice and in buffer of pH 7.4. These studies were carried out at 37 and 48°C by using standard dissolution apparatus. It has been found that in case of magnesium oxide, magnesium trisilicate and sodium bicarbonate, availability of glicIazide as well as glibenclamide enhanced while rest of the antacids retarded the availability of glic!azide and glibenclamide.
H2-receptor antagonists used in present studies are cimetidine, ranitidine, famotidine and nizatidine. These interaction studies were also carried out in simulated gastric juice and in buffer of pH 7.4 at 37 & 48°C. The availability of gliclazide and glibenclamide both were decreased considerably in presence of all of these H2-receptor antagonists, except in case of glibenclamide with nizatidine in buffer of pH 7.4, no interaction resulted between these drugs at both the temperatures.
Gliclazide, glibenclamide and all the H2-receptor antagonists were quantitated by UV spectrophotometric measurements at their respective גּ.max. In case of drug interaction studies, both the interacting drugs were quantitated simultaneously by measuring the absorbance at their respective גּ.max and using simultaneous equation. Moreover, an attempt has been made to develop a new method for routine monitoring of glibenclamide. The method is based on high performance thin layer chromatography and is rapid, quick, efficient and reliable
In vitro availability studies of glibenclamide and gliclazide were further carried out in presence of various essential and trace elements. The elements used were magnesium, calcium, chromium, manganese, iron, cobalt, nickel, copper, zinc and cadmium in the form of their hydrated salts. These studies were carried out in simulated gastric juice at variable temperatures at 37, 48 and 60°C on the B.P. dissolution test apparatus. Manganese showed maximum complexation at 48°C with gliclazide and minimum complexation was seen with nickel at 60°C, while in case of glibenclamide, cobalt exhibited maximum complexation. These studies were further extended to interactions of NIDDM drugs with these elements at various pH ranging from 1-9. It is evident from these studies that both the drugs formed metal complexes at acidic pH.
Synthesis of drug metal complexes of gliclazide and glibenc1amide were also carried out with these essential and trace elements. These synthesized complexes were analyzed for their purity, melting points, solubility in various polar and non-polar solvents and their structures studied by using various spectrophotometric techniques like IR, UV, NMR and AA in order to ascertain the site .of coordinating ligand. From these studies it has been found that glic1azide formed complexes with magnesium, calcium, chromium, manganese, iron, nickel, copper, zinc and cadmium while glibenclamide formed complexes with magnesium, chromium, cobalt, nickel, zinc and cadmium.
Furthermore, an attempt was also made to crystallize these NIDDM drugs and their complexes in various solvents. As a result of this, glic1azide and glibenc1amide both were obtained in the pure and crystalline form. X-ray crystallographic studies of these crystals were carried using x-ray diffraction spectrometer. These x-ray crystallographic studies have not been reported earlier.