Pharmacokinetics of oltipraz in rat models of diabetes mellitus induced by alloxan or streptozotocin.
Pharmacokinetic parameters of oltipraz were compared after intravenous (10 mg/kg) and oral (30 mg/kg) administration in rat model of diabetes mellitus induced by alloxan (rat model of DMIA) or streptozotocin (rat model of DMIS) and their respective control male Sprague-Dawley rats. In rat models of DMIA and DMIS, the expressions and mRNA levels of CYP1A2, 2B1/2, and 3A1(23) increased, and oltipraz was metabolized mainly via CYP1A1/2, 2B1/2, 2C11, 2D1, and 3A1/2 in male Sprague-Dawley rats. Hence, it would be expected that the AUC and CL values of oltipraz would be significantly smaller and faster, respectively, in rat models of diabetes. This was proven by the following results. After intravenous administration, the AUC values were significantly smaller in rat models of DMIA (40.1% decrease) and DMIS (26.0% decrease) than those in respective control rats, and this could be due to significantly faster CL values in rat models of DMIA (40.1% increase) and DMIS (26.0% increase). The faster CL could be due to increase in hepatic blood flow rate and significantly faster CL(int) in rat models of diabetes, since oltipraz is an intermediate hepatic extraction ratio drug in male Sprague-Dawley rats. After oral administration, the AUC values of oltipraz were also significantly smaller in rat models of DMIA (54.0% decrease) and DMIS (63.2% decrease). This could be due to increase in hepatic blood flow rate, significantly faster CL(int), and changes in the intestinal first-pass effect in rat models of diabetes. However, this was not due to decrease in absorption in rat models of diabetes.
Bae
Soo Kyung
SK
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, Republic of Korea.
Kim
Ji Young
JY
Yang
Si Hyung
SH
Kim
Jin Wan
JW
Kim
Taekrho
T
Lee
Myung Gull
MG
D000284:Administration, Oral; D000496:Alloxan; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D006207:Half-Life; D007275:Injections, Intravenous; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D011485:Protein Binding; D011719:Pyrazines / Q000493:pharmacokinetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin; D013871:Thiones; D013876:Thiophenes
D001798:Blood Proteins; D011719:Pyrazines; D012333:RNA, Messenger; D013871:Thiones; D013876:Thiophenes; D013311:Streptozocin; C026209:oltipraz; D000496:Alloxan