The potentiation and broadening the effect of low molecular hypoglycemic drugs through interaction with some CNS stimulant molecules

Abstract

The in-vitro study on the interaction of caffeine and theophylline with gliclazide, glipizide, glyburide and metformin has been carried out by IR spectroscopy, UV spectrophotometric, continuous variation, mole ratio, conductometric and Ardon’s spectrophotometric methods at room temperature and at different pHs to investigate the invitro complex formation and also to study the nature & strength of complexes which could be formed due to interaction of caffeine and theophylline with gliclazide, glipizide, glyburide and metformin. The results of the present study indicated that caffeine and theophylline form 1:1 complexes with gliclazide, glipizide, glyburide and metformin. Observations of infrared and ultraviolat spectral data have revealed the possibility of interaction of caffeine and theophylline with gliclazide, glipizide, glyburide and metformin. The spectra of target molecules alone and the 1:1 mixture of caffeine and theophylline each with gliclazide, glipizide, glyburide or metformin showed significant changes in their absorption intensities including some shifts in the absorption maxima. This may be due to interaction of caffeine and theophylline with the drugs that alter the absorption intensities. Study of continuous-variation, mole-ratio and conductometric methods has indicated initial complexation. Continuous-variation plots have conformed the formation of 1:1 complexes of caffeine with gliclazide, glipizide & metformin, 1:2 complexes of caffeine with glyburide, the formation of 2:1 complexes of theophylline with gliclazide & glipizide, 1:2 complexes of theophylline with glyburide and 1:1 complexes of theophylline with metformin. Mole-ratio plots conformed the formation of 1:1 complexes of caffeine with gliclazide, glipizide & metformin, 1:2 complexes of caffeine with glyburide, the formation of 1:2 complexes of theophylline with gliclazide & glipizide, 1:2 complexes of theophylline with glyburide & metformin.The conductometric method was used to further ascertain about the nature of interaction and stoichiometries. Conductometric titrations in demineralized water system at differe0nt pHs were carried out to find out the molar ratios at which complexation occurred. Conductrometric titrations have showed that 1:1 complexes are formed between caffeine and each of the interacting species. It has also showed that 1:1 complexes are formed between theophylline and each of the interacting species. The Ardon’s spectrophotometric method confirmed the formation of 1:1 molecular complexes and led to calculate the stability constants. It has been observed that the stability constants for caffeine-gliclazide system were higher than that of caffeine-glipizide, caffeine-glyburide, caffeine-metformin, theophylline-gliclazide, theophylline-glipizide, theophylline-glyburide and theophylline-metformin system in all pHs conditions. The in-vitro study of protein binding of gliclazide, glipizide, glyburide, metformin and their 1:1 mixtures with caffeine and theophylline have been conducted by equilibrium dialysis method performing measurement by direct spectrophotometric method at temperature 370 ± 0.50 C and at pH 7.4. The number of binding sites and affinity constants of gliclazide, glipizide, glyburide, metformin and their 1:1 mixtures with caffeine and theophylline have been calculated by scatchard method.Scatchard plots were prepared to reveal the number of binding sites and the affinity for protein binding. It has been found that both caffeine and theophylline cause lowering the affinity and percentage of binding of the drugs in the mixture to bovine serum albumin. Thus, the interaction of gliclazide, glipizide, glyburide and metformin with caffeine and theophylline can increase the free drug concentration of gliclazide, glipizide, glyburide and metformin in blood plasma. This may change the pharmacokinetic and pharmacodynamic properties of the drugs. An in-vivo study has been conducted in rats to observe the influence of caffeine and theophylline on plasma concentration of gliclazide, glipizide, glyburide and metformin. The plasma concentration of gliclazide, glipizide, glyburide and metformin were determined by UV spectrophotometric method after oral single administration of gliclazide, glipizide, glyburide, metformin alone and with caffeine & theophylline in rats. The in-vivo study for determination of plasma cocentration showed that concurrent administration of caffeine and theophylline with gliclazide and glyburide have not made noticeable changes in plasma concentration of gliclazide and glyburide. But administration of caffeine and theophylline with glipizide and metformin in rats has showed a significant change in plasma concentration of glipizide and metformin. So, a competitive inhibition of the binding to plasma protein by caffeine and theophylline increases the plasma concentration of glipizide and metformin.Thus any change in plasma concentration may affect the pharmacological effects of the drug. An in-vivo study has been conducted in rats to observe the effect of caffeine and theophylline on hypoglycemic activity of gliclazide, glipizide, glyburide and metformin. The blood sugar levels of animals were measured after administration of a drug alone and in combination. The blood sugar levels were estimated in two stages; firstly, after 2 weeks and secondly, after 4 weeks of the administration of drug. The results in this study have shown that caffeine and theophylline can enhance hypoglycemic effect of gliclazide, glipizide, glyburide and metformin in rats. It has also been found that the influence of caffeine on metformin is stronger than on gliclazide, glipizide and glyburide in respect of hypoglycemic activity.Thus, the hypoglycemic activities of gliclazide, glipizide, glyburide and metformin are potentiated and broadened by caffeine and theophylline concurrent application. The potentiation of the antidiabetic properties of gliclazide, glipizide, glyburide and metformin may be due to relaxation effect of caffeine and theophylline on smooth muscles of the rat as well as some sort of modification of the molecular conformations of the antidiabetic agents. Thus, the interaction of caffeine and theophylline with the potent antidiabetic drugs gliclazide, glipizide, glyburide and metformin hydrochloride may greatly influence the activity of these molecules. The data obtained from the present study would help to recommend that low molecular hypoglycemic drugs gliclazide, glipizide, glyburide as well as metformin may result into compatible combination therapies with CNS stimulant molecules caffeine and theophylline.