|
KMID : 0043320080310030406
|
|
Archives of Pharmacal Research
2008 Volume.31 No. 3 p.406 ~ p.413
|
|
|
In Vitro Metabolic Stability of Moisture-Sensitive Rabeprazole in Human Liver Microsomes and Its Modulation by Pharmaceutical Excipients
|
|
Ren Shan
Park Mi-Jin
Kim Ae-Ra
Lee Beom-Jin
|
|
|
Abstract
|
|
|
|
A reliable method to assess in vitro metabolic stability of rabeprazole and its modulation by Generally Recognized As Safe (GRAS)-listed pharmaceutical excipients was established in human liver microsomes. The metabolic stability of rabeprazole decreased as a function of incubation time, resulting in the formation of thioether rabeprazole via nonenzymatic degradation and enzymatic metabolism, Buffer type was also a determining factor for the degree of both nonenzymatic degradation and enzymatic and enzymatic metabolism. The net extent of enzymatic drug metabolism, obtained by calculating the difference in drug degradation between a microsome-present reaction System and a microsome-free solution, was about % in phosphate buffer and % in Tris buffer, respectively. Rabeprazole exhibited first-order kinetics in Microsome-free solution but showed non-linear kinetics in the microsome-present reaction system. The maximal velocity, in phosphate buffer was 5.07 and the michaelis-Menten constant, , was 10.39 by computer-fitting to the classical Michaelis-Menten equation for pattern of time-dependent change in the substrate concentration. The intact drug and its thioether form were well resolved and successfully identified by HPLC chromatography and liquid chromatography mass spectroscopy (LC/MS). The metabolic stability of rabeprazole was also modulated by the presence of pharmaceutical excipients. Among the five pharmaceutical excipients tested, poloxamer 188 and Gelucire 44/14 had potentially inhibitory effects on rabeprazole metabolism in human liver microsomes (p < 0.05). A greater understanding of metabolic stability and its modulation by pharmaceutical excipients would be useful for optimizing the bioavailability of rabeprazole at the early formulation stages.
|
|
|
KEYWORD
|
|
|
Rabeprazole, Thioether form, Pharmaceutical excipients, Metabolic stability, Human liver Microsomes
|
|
|
FullTexts / Linksout information
|
|
|
|
|
|
Listed journal information
|
|
  
|