Effect of CYP3A1(23) Induction on Clarithromycin Pharmacokinetics in Rats with Diabetes Mellitus

Abstract

After intravenous and oral administration of clarithromycin at a dose of 20 mg/kg of body weight to rats with diabetes mellitus induced by alloxan (DMIA) and diabetes mellitus induced by streptozotocin (DMIS), the area under the curve values were significantly smaller than those of respective control rats. The in vitro intrinsic clearance values for the disappearance of clarithromycin were significantly faster in both rats with DMIA and rats with DMIS than in control rats. The above data suggested that metabolism of clarithromycin increased in both types of diabetic rat due to an increase in the expression and mRNA level of CYP3A1(23) in the rats.Animal models of insulin-dependent diabetes mellitus induced by administration of several chemicals, principally alloxan, streptozotocin, and zinc chelators, have been reported (22, 30). There are major differences in the diabetic effects of streptozotocin and alloxan (reference 30 and references therein). It is known that structural alterations in pancreatic beta cells (total degranulation) occur within 48 h after administration of streptozotocin and last up to 4 months. Alloxan causes a decrease in hepatic glycogen within 24 to 72 h, an effect that is partially reversible by insulin. Alloxan generally produces greater cytotoxicity owing to its conversion to anionic radicals.For rats with diabetes mellitus induced by streptozotocin (DMIS), a decreased bile flow rate and altered bile compositions (3), hepatotoxicity (31), and impaired kidney function (18, 21) have been reported. Glucuronidation and sulfation were also profoundly affected by DMIS in rats (23). In rats with diabetes mellitus induced by alloxan (DMIA), kidney function was also impaired (12,20).A previous study (13) has shown that the expression of hepatic microsomal cytochrome P450 (CYP) 1A2, 2B1/2, 2E1, and 3A23 increased 2.8, 1.8, 3.0, and 1.5 times, respectively, in rats with DMIA compared to controls, whereas the expression of CYP2C11 decreased to 23% of the control value. Similarly, the expression of CYP1A2, 2B1/2, 2E1, and 3A23 also increased 3.1, 3.3, 2.8, and 1.9 times, respectively, in rats with DMIS compared to controls, whereas the expression of CYP2C11 decreased to 37% of the control value. 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 rats with DMIA compared to controls, whereas CYP2C11 decreased to 31% of the control value. 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 rats with DMIS compared to controls, whereas CYP2C11 decreased to 28% of the control value. Similar changes in some of the above-mentioned CYP isozymes have also been reported for rats with DMIA and/or DMIS (8,15,(24)(25)(26)(27)32).It has been reported that CYP3A1 (23) is involved in the metabolism of clarithromycin in rats (14). Hence, it would be expected that pharmacokinetics of clarithromycin could be changed in rats with DMIA and DMIS due to an increase in the expression and...

Opposite Effect of Diabetes Mellitus Induced by Streptozotocin on Oral and Intravenous Pharmacokinetics of Verapamil in Rats

“…It was reported that the enzyme activity, protein expression, and/or mRNA level of hepatic CYP3A1 (Kim et al, 2005b;Borbás et al, 2006) and CYP3A2 in streptozotocin (STZ)-induced diabetic rats (Shimojo et al, 1993;Borbás et al, 2006) were higher than those in control rats. Several reports showed that the up-regulation of hepatic CYP3A in diabetic rats may contribute to the faster clearance and lower area under the concentration-time curve (AUC) value of drugs, such as telithromycin and clarithromycin (Kim et al, 2005b;Lee and Lee, 2008). It is known that the small intestine also plays an important role in first-pass extraction of orally ingested xenobiotics.…”

Combined Contribution of Increased Intestinal Permeability and Inhibited Deglycosylation of Ginsenoside Rb1 in the Intestinal Tract to the Enhancement of Ginsenoside Rb1 Exposure in Diabetic Rats after Oral Administration

“…For example, faster clearance and a lower area under the concentration-time curve (AUC) of telithromycin and clarithromycin were shown in diabetic rats (Kim et al, 2005;Lee and Lee, 2008). In another study, diabetes induced increased the plasma concentration of verapamil after oral administration .…”

Effects ofSaccharomyces boulardiion antibiotic induced orocecal transit in rats

“…Clarithromycin and S. boulardii were dissolved in saline. The dose selection of the test drugs were according to the previous in vivo rat studies (Buts et al, 1990;Kim et al, 2005).…”