No 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...

Dose-independent pharmacokinetics of oltipraz after intravenous and/or oral administration at various doses to mice, rats, rabbits and dogs were evaluated. After both intravenous and/or oral administration of oltipraz to mice (5, 10 and 20 mg/kg for intravenous and 15, 30 and 50 mg/kg for oral administration), rats (5, 10 and 20 mg/kg for intravenous and 25, 50 and 100 mg/kg for oral administration), rabbits (5, 10 and 30 mg/kg for intravenous administration) and dogs (5 and 10 mg/kg for intravenous and 50 and 100 mg/kg for oral administration), the total area under the plasma concentration-time curve from time zero to time infinity (AUC) values of oltipraz were dose-proportional in all animals studied. Animal scale-up of some pharmacokinetics parameters of oltipraz was also performed based on the parameters after intravenous administration at a dose of 10 mg/kg to mice, rats, rabbits and dogs. Linear relationships were obtained between log time-averaged total body clearance (Cl) x maximum life-span potential (MLP) (1 year/h) and log species body weight (W) (kg) (r=0.999; p=0.0015), log Cl (l/h) and log W (kg) (r=0.979; p=0.0209), and log apparent volume of distribution at steady state (V(ss)) (l) and log W (kg) (r=0.999; p=0.0009). The corresponding allometric equations were ClxMLP=49.8 W(0.861), Cl=5.20 W(0.523) and V(ss)=4.46 W(0.764). Interspecies scale-up of plasma concentration-time data for the four species using pharmacokinetic time of dienetichron resulted in similar profiles. In addition, concentrations of oltipraz in a plasma concentration-time profile for humans predicted using the four animal data fitted to the dienetichron time transformation of animal data.

In order to find out what types of the hepatic microsomal cytochrome P450 (CYP) isozymes are involved in the metabolism of ipriflavone, ipriflavone at a dose of 20 mg kg(-1) (or 15 mg kg(-1)) was infused in male Sprague-Dawley rats. In rats pretreated with SKF 525-A (a non-specific CYP isozyme inhibitor in rats), the total body clearance (CL) of ipriflavone was significantly slower (29.9% decrease) than that in control rats. This indicates that ipriflavone is metabolized via CYP isozymes in rats, hence various enzyme inducers and inhibitors were used in in-vitro or in-vivo studies in rats. In rats pretreated with 3-methylcholanthrene and phenobarbital (main inducers of CYP1A1/2 and 2B1/2 in rats, respectively), the CL values were significantly higher (153 and 67.2% increases, respectively). In rats pretreated with sulfaphenazole (a main inhibitor of CYP2C11 in rats), the CL was significantly slower (22.5% decrease) than that in control rats. On addition of furafylline (a main inhibitor of CYP1A2 in rats), the in-vitro intrinsic clearance for the disappearance of ipriflavone was significantly slower (50.8% decrease) than that without furafylline. However, the CL values were not significantly different in rats pretreated with orphenadrine and isoniazid (a main inducer of CYP2E1 in rats), and quinine and troleandomycin (main inhibitors of CYP2D1 and 3A23/2 in rats, respectively) compared to controls. These data suggest that ipriflavone could be metabolized mainly via CYP1A1/2, 2B1/2 and 2C11 in rats.

The goal of our study was to demonstrate the spectrum of genomic alterations present in the residual disease of patients with advanced high-grade serous ovarian cancer (HGSOC) after neoadjuvant chemotherapy (NAC), including matched pretreatment biopsies. During the study period between 2006 and 2017, we collected pre-NAC and post-NAC tumor tissue samples from patients with advanced HGSOC. We performed combined next-generation sequencing and immunohistochemistry to identify actionable targets and pathway activation in post-NAC residual tumors. We also examined whether post-NAC profiling of residual HGSOC identified targetable molecular lesions in the chemotherapy-resistant component of tumors. Among 102 post-NAC samples, 41 (40%) of patients had mutations in homologous recombination repair (HRR) genes (HRR deficiency). Patients with HRR mutations had higher tumor mutation burdens (p < 0.001) and higher alterations in the PI3K-AKT-mTOR pathway (p = 0.004) than patients without these HRR mutations. Nevertheless, we found no significant differences in progression-free survival (p = 0.662) and overall survival (OS; p = 0.828) between the two groups. Most patients (91%) had alterations in at least one of the targetable pathways, and those patients with cell cycle (p = 0.004) and PI3K-AKT-mTOR signaling (p = 0.005) pathway alterations had poorer OS (Bonferroni-corrected threshold = 0.0083, 0.05/6). We showed the genomic landscape of tumor cells remaining in advanced HGSOC after NAC. Once validated, these data can help inform biomarker-driven adjuvant studies in targeting residual tumors to improve the outcomes of patients with advanced HGSOC after NAC.