In vitro and In vivo Interaction Study between Ketotifen Fumarate and Metformin Hydrochloride

Abstract

The objectives of the present study were to investigate the drug-drug interactions between ketotifen fumarate and metformin hydrochloride. The in vitro results were
correlated with in vivo model to see whether the desired drug concentration could attain into the blood stream or not. Finally attempts have been taken to find out the effects of these complexes on the liver and kidney. Each of the drugs absorption was analyzed in the UV-VIS region. The spectra of pure drugs as well as their 1:1, 1:2 and 2:1 mixtures of ketotifen and metformin, were studied at pHs 2.0, 2.8, and 7.4. When ketotifen was mixed with metformin, a sharp change was observed in the curve at pHs 2.8 & 7.4 which indicated drug-drug interactions, whereas the absence of such particular breakdown in the curve of ketotifen and metformin mixture at pH 2.0 revealed the absence of drug interactions. The stability constant values (k = 1x10-2) for the particular interaction was determined by graphical representation of Ardon’s plot. The stability constants of ketotifen and metformin were 0.05, 0.01 and 0.77 at pH 2.0, 2.8, 7.4 respectively. On the other hand, DSC of the samples (ketotifen, metformin and ketotifen-metformin mixture) were performed and observed that ketotifen-metformin complex exhibited a sharp new peak at 123.04oC (-2.61 mW/mg). The Rf values of ketotifen (0.49) and metformin (0.51) was found to be completely different from ketotifen-metformin mixture (0.39) which conclude the stability of the complex for both mixtures. The results of investigation of hepatotoxicity of combination drug therapy were compared with single drug sample ketotifen. But the groups which receive the combination drug samples ketotifen and metforin (67.5 + 1.44 IU/L) showed a significant increase in SGPOT, and showed a significant decrease of ATPN levels ketotifen and metformin mixture (6.13 + 0.73 IU/L). Now we can conclude that the patients who had been suffering from diabetes should take a precaution during coadministration of ketotifen fumarate and metformin hydrochloride.