Pharmacokinetics of oltipraz in rat models of diabetes mellitus induced by alloxan or streptozotocin Soo Kyung Bae a , Ji Young Kim a , Si Hyung Yang a , Jin Wan Kim b , Taekrho Kim b , Myung Gull Lee a, * a 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 b R and D Center of Pharmaceuticals, Institute of Science and Technology, CJ Corporation, San 522-1, Ichon, Kyunggi-Do 467-810, Republic of Korea Received 23 May 2005; accepted 16 September 2005 Abstract 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. D 2005 Elsevier Inc. All rights reserved. Keywords: Oltipraz; Pharmacokinetics; Diabetes mellitus; Alloxan or streptozotocin; Rats Introduction Kim et al. (2005a) reported that the expressions of hepatic microsomal cytochrome P450 (CYP) 1A2, 2B1/2, 2E1, and 3A1(23) increased 2.8, 1.8, 3.0, and 1.5 times, respectively, in male Sprague–Dawley rat model of diabetes mellitus induced by alloxan (rat model of DMIA) as compared to controls, whereas the expression of CYP2C11 decreased to 23% of control based on Western blot analysis. Similarly, the expres- sions of CYP1A2, 2B1/2, 2E1, and 3A23 also increased 3.1, 3.3, 2.8, and 1.9 times, respectively, in rat model of diabetes mellitus induced by streptozotocin (rat model of DMIS) as compared to controls, whereas the expression of CYP2C11 decreased to 37% of control. The mRNA levels of CYP1A2, 2B1, 2B2, 2E1, and 3A23 increased 3.4, 1.9, 1.6, 4.3, and 1.6 times, respectively, in rat model of DMIA as compared to controls, whereas the mRNA level of CYP2C11 decreased to 31% of control based on Northern blot analysis. Similarly, the mRNA levels of CYP1A2, 2B1, 2B2, 2E1, and 3A23 also increased 4.2, 3.9, 1.9, 3.6, and 2.2 times, respectively, in rat model of DMIS as compared to controls, whereas the mRNA level of CYP2C11 decreased to 28% of control. Similar changes in some of the above mentioned CYP isozymes were also reported in rat models of DMIA and/or DMIS (Song et al., 1987; Dong et al., 1988; Yamazoe et al., 1989; Thummel and Schenkman, 1990; Raza et al., 1996; Li and Zhang, 1998). Oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione], a synthetic dithiolthione, has been developed by Rho ˆne–Poulenc (Virty-sur-Seine, France) for the treatment of schistosomiasis 0024-3205/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.lfs.2005.09.031 * Corresponding author. Tel.: +82 2 880 7855; fax: +82 2 889 8693. E-mail address: leemg@snu.ac.kr (M.G. Lee). Life Sciences 78 (2006) 2287 – 2294 www.elsevier.com/locate/lifescie