A predictive biomarker for altered 5‐fluorouracil pharmacokinetics following repeated administration in a rat model of colorectal cancer

The relationship between the plasma ratio of dihydrouracil/uracil (UH2/Ura) and hepatic dihydropyrimidine dehydrogenase (DPD) activity after repeated 5‐fluorouracil (5‐FU) treatment in rats with colorectal cancer (CRC) was investigated. Repeated intravenous 5‐FU bolus injections resulted in a significant decrease in the total clearance (CL_tot) and an increased area under the curve (AUC_0‐∞) in CRC rats. Furthermore, the hepatic DPD levels and the plasma ratio of UH2/Ura decreased significantly and lost their circadian rhythms in CRC rats treated repeatedly with 5‐FU, although significant circadian variation in the two parameters was observed in the control CRC rats. Moreover, a significant correlation was found between the plasma ratio of UH2/Ura and hepatic DPD activity in CRC rats untreated and treated with single or repeated 5‐FU administration (r² = 0.865, p < 0.01). The ratio of UH2/Ura in plasma could be a predictive biomarker of the suppression of hepatic DPD levels during repeated 5‐FU‐based treatment. Furthermore, by plotting the observed pharmacokinetic parameters of 5‐FU against hepatic DPD activity levels predicted by the ratio of UH2/Ura in plasma, AUC_0‐∞, CL_tot and half‐life (t_1/2) were closely linked to predicted hepatic DPD activity levels. These observations suggest that the factor that significantly influences the AUC_0‐∞, CL_tot and t_1/2 of 5‐FU after single or repeated administration of 5‐FU is the hepatic DPD activity and it could be assessed by the ratio of UH2/Ura in plasma. Copyright © 2013 John Wiley & Sons, Ltd.     

Probiotic Bifidobacterium bifidum G9‐1 attenuates 5‐fluorouracil‐induced intestinal mucositis in mice via suppression of dysbiosis‐related secondary inflammatory responses

Bifidobacterium, a major component of the intestinal microbiota, has been clinically used for the treatment of diarrhoea and constipation. 5‐Fluorouracil (5‐FU), widely used for cancer chemotherapy, is known to frequently induce intestinal mucositis accompanied by severe diarrhoea. The present study examined the effect of Bifidobacterium bifidum G9‐1 (BBG9‐1) on 5‐FU‐induced intestinal mucositis in mice. Intestinal mucositis was induced by repeated administration of 5‐FU for 6 days. BBG9‐1 was administered orally once daily for 9 days, beginning 3 days before the onset of 5‐FU treatment. Repeated administration of 5‐FU caused severe intestinal mucositis, characterised by shortening of villi and destruction of crypts, accompanied by increases in intestinal myeloperoxidase activity and inflammatory cytokine expression, body weight loss, and diarrhoea on day 6. Daily administration of BBG9‐1 significantly reduced the severity of intestinal mucositis and inflammatory responses and tended to attenuate clinical symptoms. In contrast, BBG9‐1 failed to prevent apoptosis induction on day 1 after the first 5‐FU administration. The structure of the intestinal microbiota, as analysed by weighted UniFrac distance, was largely altered by 5‐FU treatment, but this change was mitigated by daily administration of BBG9‐1. Moreover, 5‐FU treatment decreased the abundance of Firmicutes and increased the abundance of Bacteroidetes, but these responses were also significantly inhibited by daily administration of BBG9‐1. These results suggest that BBG9‐1 has an ameliorative effect against 5‐FU‐induced intestinal mucositis through the attenuation of inflammatory responses via improve dysbiosis. BBG9‐1 could be useful for the prevention of intestinal mucositis during cancer chemotherapy.     

Effect of acute hepatic failure on the hepatic first‐pass effect of 5‐fluorouracil in rats

Objectives In cancer chemotherapy for hepatocellular carcinoma, 5‐fluorouracil is widely used and has typically been given by intrahepatic arterial (i.a.) infusion to increase treatment efficacy and reduce systemic toxicity. 5‐Fluorouracil is eliminated primarily by the liver and so the hepatic first‐pass effect after intrahepatic arterial administration of 5‐fluorouracil may be lower in patients with hepatic failure, and systemic toxicity may not be reduced. In this study, we have investigated the effect of acute hepatic failure on the first‐pass effect of 5‐fluorouracil in rats. Methods Experimental acute hepatic failure was induced by treatment with carbon tetrachloride (CCl₄). 5‐Fluorouracil was infused for 15 min into the hepatic artery or the saphenous vein of rats at a dose of 1.25 mg/kg. Key findings Hepatic availability in 50% CCl₄‐treated (severe hepatic failure) rats was higher than in controls. Conclusions The hepatic first‐pass effect after intrahepatic arterial administration of 5‐fluorouracil was lower in severe hepatic failure. Therefore, the reducing effect of the systemic toxicity after intrahepatic arterial administration may be lower in severe hepatic failure.     

Role of peptide YY in 5‐fluorouracil‐induced reduction of dietary intake

5‐fluorouracil (5‐FU) is part of the standard care for cancer treatment but is associated with high incidences of appetite loss and reduced food intake, which may contribute to chemotherapy‐induced cachexia (weakness and wasting of tissue). The role of gastrointestinal satiety hormones in chemotherapy‐induced appetite loss has not been intensively investigated. Peptide YY (PYY) and glucagon‐like peptide (GLP)‐1 are important signals of gastrointestinal satiety, so this study examined the roles of these gut hormones in 5‐FU‐induced reduction of dietary intake. Mice were given 5‐FU (50 mg/kg, intraperitoneal [i.p.]) every day for 4 consecutive days. Gene expression levels of proglucagon (Pro‐Gcg), a precursor of GLP‐1, and PYY in the colon were examined by real‐time RT‐PCR. Serum levels of GLP‐1 and PYY were measured by enzyme‐linked immunosorbent assay. Some mice were pretreated with the GLP‐1 receptor antagonist exendin9–39 (1 mg/kg) or the neuropeptide Y type 2 (NPY2) receptor antagonist BIIE0246 (2 mg/kg) via the i.p. route 30 minutes before 5‐FU administration. Mice receiving 5‐FU exhibited a significant reduction in food intake that was correlated with body weight loss. These mice also showed significantly enhanced expression levels of mRNAs encoding pro‐GLP‐1 and PYY in the transverse and distal colon as well as elevated serum concentrations of GLP‐1 and PYY compared to vehicle‐treated controls. The 5‐FU‐induced reduction in food intake was attenuated by BIIE0246 but not by exendin9–39. These data suggest that administration of a NPY2 receptor antagonist may be effective for attenuating the anorexia caused by 5‐FU chemotherapy.     

Preparation and characterization of 5‐fluorouracil‐loaded poly(ϵ‐caprolactone) microspheres for drug administration

Microspheres of 5‐fluorouracil‐loaded poly(?‐caprolactone) (PCL) were prepared by spray‐drying procedure. The degradation characteristics and 5‐fluorouracil release in vitro as well as in vivo were investigated. The average molecular weight, weight loss, crystallinity, and morphology of microspheres were determined using GPC, DSC, and SEM, at different times during the in vitro degradation process. The size distribution of the microspheres indicated that most of the particles were smaller than 3 µm. A 30% weight loss as well as an increase of crystallinity were observed on day 330 of incubation. The percentage of entrapment efficiency of 5‐FU was 49% (44 µg of drug/mg of microspheres). The in vitro total release of 5‐FU took place in 8 days. Determination of plasma 5‐FU concentration in vivo using s.c. injection of 5‐FU‐loaded microspheres in Wistar rats by HPLC with analysis of data using a non‐compartmental model showed drug in plasma 18 days after administration with a maximum drug concentration of 1.5 µg/ml at 96 h. Pharmacokineticallly, a significant increase of AUC and MRT of 5‐FU with regard to the administration of the drug in solution. Scanning electron microscopy and histological studies indicated that the microspheres were surrounded by connective tissue and inflammatory processes were not evident. As a result of these characteristics, the 5‐FU‐loaded PCL microspheres could be used for drug delivery. Drug Dev Res 63:41–53, 2004. © 2004 Wiley‐Liss, Inc.     

Effect of gastrectomy on the pharmacokinetics of 5-fluorouracil and gimeracil after oral administration of S-1

The effect of gastrectomy on pharmacokinetics after S-1 administration was investigated in a total of 12 cases - nine in which partial gastrectomy was performed and three in which total gastrectomy was performed. A single oral dose of S-1, 50 mg as tegafur, was administered, serial peripheral blood samples were collected, and the concentrations of 5-fluorouracil (5-FU) and gimeracil (CDHP) were measured. The pre-operative S-1 dose was administered about 7 days before surgery and the post-operative dose was administered around post-operative hospital day 14. In the partial gastrectomy cases the maximum post-operative blood concentration (Cmax) of 5-FU and CDHP tended to be lower than before surgery, and the difference in 5-FU concentrations was significant. The area under the blood concentration-time curve (AUC0-8 h) for CDHP was significantly smaller post- than pre-operatively, but no significant difference was observed with regard to 5-FU. In the total gastrectomy cases the post-operative tmax of both 5-FU and CDHP was shorter than the pre-operative tmax, and no significant differences were observed between the pre- and post-operative AUC0-8 h values. Thus, the results of the present study showed that around post-operative hospital day 14, when total oral feeding had become possible after surgery for gastric cancer, the AUC0-8 h values of 5-FU and CDHP after S-1 administration were almost the same as before surgery and that gastrectomy had hardly any effect on the pharmacokinetics of S-1.     

Hepatic fibrosis does not affect the pharmacokinetics of 5-fluorouracil in rats

In the case of cancer chemotherapy for hepatocellular carcinoma, 5‐fluorouracil (5‐FU) is used widely, and has typically been given by intrahepatic arterial (i.a.) infusion to increase treatment efficacy and to reduce systemic toxicity. 5‐Fluorouracil is eliminated primarily by the liver, and so its use in patients with hepatic disease can be difficult. This study investigated the effect of hepatic fibrosis on the pharmacokinetics of 5‐FU in rats. Experimental hepatic fibrosis was induced by carbon tetrachloride treatment. 5‐Fluorouracil was infused for 15 min into the hepatic artery or the saphenous vein of the rats at a dose of 1.25 mg/kg. There were no significant differences in the plasma concentration and AUC of 5‐FU between hepatic disease rats and their controls after both intravenous and intraarterial injection. This result is probably attributed to the fact that there were no significant differences in hepatic blood flow and dihydropyrimidine dehydrogenase (DPD; an initial and rate‐limiting enzyme in 5‐FU catabolism) activity between hepatic disease rats and their controls, because the total clearance of 5‐FU after intravenous and intraarterial administration is mainly limited by hepatic blood flow and DPD activity, respectively. In conclusion, the pharmacokinetics of 5‐FU is not affected by hepatic fibrosis, unlike that of many hepatically metabolized drugs. Copyright © 2010 John Wiley & Sons, Ltd.     

5‐Fluorouracil treatment alters the expression of intestinal transporters in rats

5‐Fluorouracil (5‐FU), an anticancer drug, causes severe gastrointestinal damage, which may affect the absorption of orally administered drugs including the substrates of intestinal uptake and efflux transporters. This study aimed to investigate quantitatively the effect of 5‐FU‐induced intestinal damage on the expression of intestinal transporters: P‐glycoprotein (P‐gp), breast cancer resistance protein (BCRP) and peptide transporter 1 (PEPT1) in rats. The rats were treated with 5‐FU (30 mg/kg/day, p.o. ) for 5 days to induce intestinal damage, and then the upper, middle and lower intestinal segments were removed. The mRNA and protein expression levels of these transporters in each segment were determined using quantitative real‐time PCR and Western blotting, respectively. In the 5‐FU‐treated rats, the protein levels of P‐gp and Bcrp in the upper segment were significantly increased to 15‐ and 2.6‐fold of the control, respectively, while those in other segments were unaffected. Pept1 expression was increased by 5‐FU in almost all segments. A remarkable increase in P‐gp expression was shown, the uptake of digoxin, a P‐gp substrate, in each intestinal segment was measured using a rat everted sac. As a result, the uptake of digoxin in the upper segments of 5‐FU‐treated rats was decreased compared with that of the control. In conclusion, 5‐FU‐induced intestinal damage was shown to alter the expression of these transporters, especially in the upper intestinal segment, while the characteristics of the influence varied among the transporters. The 5‐FU‐induced intestinal damage may affect transporter‐mediated drug absorption of orally administered drugs in the clinical setting.     

In‐situ absorption,protein binding and pharmacokinetic studies of S002‐853, a novel antidiabetic and antidyslipidaemic flavone derivative in rats

Objectives The aim of the study was to investigate the in‐situ absorption kinetics, plasma protein binding and pharmacokinetic characteristics of a novel synthetic flavone derivative, S002‐853, which shows pronounced antidiabetic and antidyslipidaemic activity. Methods Quantification of S002‐853 in plasma was performed by the LC‐MS/MS method and in‐situ sample analysis was carried out by the HPLC‐UV method. Key findings The absorption rate constant was 0.274/h in a mild alkaline environment, which S002‐853 experiences in the intestine following oral dose administration. Plasma protein binding was found to be 26.37 ± 2.58% at a concentration of 1 μg/ml. The pharmacokinetic parameters were determined in male rats after administration of a single 40 mg/kg oral dose and 10 mg/kg intravenous dose. The peak plasma concentration (C_max) was found to be 60.93 ng/ml at 8 h after oral administration. Irregular concentration–time profiles with secondary peaks were observed after oral dose administration. The elimination half‐life of the compound was 19.56 h and 16.30 h after oral and intravenous doses, respectively. Comparison of the AUC after oral and intravenous dosing of S002‐853 indicates that only about 29.48% (bioavailability) of the oral dose reaches the systemic circulation. Conclusions In‐situ study of S002‐853 shows slow absorption from the gastrointestinal tract. S002‐853 also shows low plasma protein binding. The pharmacokinetic parameters after oral and intravenous dose reveal low oral bioavailability and high mean residence time.     

Effect of Huang‐Lian‐Jie‐Du‐Decoction on pharmacokinetics of verapamil in rats

Objectives The aim was to investigate the effect of Huang‐Lian‐Jie‐Du‐Decoction (HLJDD) on the pharmacokinetic behaviour of verapamil in rats. Methods Rats orally received 3.33 g/kg of HLJDD extract for 14 days, and pharmacokinetics of verapamil was investigated after oral and intravenous verapamil. Norverapamil formation for assessing cytochrome P450 3A activity in hepatic and intestinal microsomes of the HLJDD‐treated rats was investigated. The inhibitory effect of berberine on the formation of norverapamil in intestinal and hepatic microsomes was also evaluated. Key findings HLJDD treatment increased the plasma concentration of verapamil and decreased the plasma concentration of norverapamil, resulting in a 24% increase in the AUC_0–480 of verapamil and a 25% reduction in the AUC_0–480 of norverapamil after oral administration. However, HLJDD did not alter the pharmacokinetic behaviour of verapamil after intravenous administration. Norverapamil formation showed biphasic kinetics in both intestinal and hepatic microsomes. HLJDD treatment significantly decreased the intrinsic clearance of verapamil in intestinal microsomes, but had no effect on the hepatic metabolism of verapamil. Berberine also inhibited norverapamil formation in both intestinal and hepatic microsomes; the extent of inhibition was larger in intestinal microsomes. Conclusions HLJDD displayed a route‐dependent effect on the pharmacokinetics of verapamil in rats. HLJDD treatment increased the bioavailability of verapamil partly via inhibiting first‐pass verapamil metabolism in the intestine.     

Evaluation of oral pharmacokinetics,in vitro metabolism,blood partitioning and plasma protein binding of novel antidiabetic agent,S009‐0629 in rats

S009‐0629 [methyl‐8‐(methylthio)‐2‐phenyl‐6‐p‐tolyl‐4,5‐dihydro‐2H‐benzo[e]indazole‐9‐carboxylate] is a novel antidiabetic agent with PTP1B inhibitory activity. In this study, we have investigated the in vitro metabolic stability, plasma protein binding, blood partitioning, and oral pharmacokinetic study of S009‐0629 in rats. The plasma protein binding, blood partitioning, and metabolic stability were determined by HPLC method. The oral pharmacokinetic study was analyzed by liquid chromatography coupled mass spectrometry (LC‐MS/MS) method. The plasma protein binding of S009‐0629 using modified charcoal adsorption method at 5 and 10 µg/mL was 80.58 ± 1.04% and 81.95 ± 1.15%, respectively. The K_RBC/PL of S009‐0629 was independent of concentration and time. The in‐vitro half‐life of S009‐0629 at 5 and 10 µM using rat liver microsomes was determined as 273 ± 24.46 and 281.67 ± 26.53 min, respectively. After oral administration, S009‐0629 exhibited C_max 55.51 ± 1.18 ng/mL was observed at 18 hr (t_max). S009‐0629 was found to have the large apparent volume of distribution (1,894.93 ± 363.67 L/kg). Oral in‐vivo t_1/2 of S009‐0629 was found to be 41.23 ± 5.96 hr. A rapid and highly sensitive LC‐MS/MS method was validated for S009‐0629 in rat plasma. S009‐0629 has high plasma protein binding and low hepatic extraction. S009‐0629 has no affinity with human P‐gp and BCRP in ATPase assay. After oral dosing, S009‐0629 has slow absorption and elimination in rats.     

Curcumin Inhibits 5‐Fluorouracil‐induced Up‐regulation of CXCL1 and CXCL2 of the Colon Associated with Attenuation of Diarrhoea Development

The compound 5‐fluorouracil (5‐FU) is used in cancer chemotherapy and is known to cause diarrhoea. We recently reported that chemokine (C‐X‐C motif) ligand 1 (CXCL1) and neutrophils in the colonic mucosa were markedly increased by the administration of 5‐FU in mice. Curcumin has anti‐inflammatory, antitumour and antioxidant properties. Therefore, we examined the effect of curcumin on 5‐FU‐induced diarrhoea development and CXCL1 and CXCL2 up‐regulation in the colon. Mice were given 5‐FU (50 mg/kg, i.p.) daily for 4 days. Curcumin (100 or 300 mg/kg, p.o.) was administered on the day before the first administration of 5‐FU and administered 30 min. before the administration of 5‐FU. Gene expression levels of CXCL1 and CXCL2 in the colon were examined by real‐time RT‐PCR. Curcumin reduced the 5‐FU‐induced diarrhoea development. Under this condition, the CXCL1 and CXCL2 gene up‐regulated by 5‐FU administration was inhibited by curcumin. The gene expression of CXCL1 and CXCL2 was also enhanced by 5‐FU application in vitro. The 5‐FU‐induced up‐regulated CXCL1 and CXCL2 gene expressions were inhibited by curcumin, Bay‐117082 and bortezomib, nuclear factor kappa B (NF‐κB) inhibitors, C646, a p300/cyclic adenosine monophosphate response element‐binding protein–histone acetyltransferase (HAT) inhibitor. In conclusion, these findings suggested that curcumin prevented the development of diarrhoea by inhibiting NF‐κB and HAT activation.     

Comparative pharmacokinetic study of paclitaxel and docetaxel in streptozotocin‐induced diabetic rats

The pharmacokinetics of paclitaxel and docetaxel were compared in diabetic rats induced by streptozotocin (DMIS rats) and the impact of altered expression of cytochrome P450 3A (Cyp3A) and P‐glycoprotein (P‐gp) in the diabetic state. The pharmacokinetics of paclitaxel and docetaxel were determined after intravenous (5 mg/kg) and oral (30 and 40 mg/kg, respectively) administration to both groups and the mRNA expression levels of Cyp3A isozymes and Mdr1a and Mdr1b in the liver and small intestine were determined in control and DMIS rats. After intravenous administration, the AUC and clearance of paclitaxel and docetaxel were not significantly different in DMIS vs control rats. After oral administration, the AUC and C_max of paclitaxel in DMIS rats were significantly greater than those in the control rats, whereas those of docetaxel was not changed significantly. The mRNA expression levels of hepatic Cyp3A1, Cyp3A9 and Mdr1b were significantly increased in DMIS compared with the control rats. In the intestine, Cyp3A62 expression decreased in the DMIS rats compared with the controls. Thus the pharmacokinetic changes of taxanes observed in the DMIS rats were attributed to changes in P‐gp and Cyp3A, predominant factors that control the absorption of paclitaxel and docetaxel, respectively. It seemed that there were different susceptibilities to intestinal P‐gp and Cyp3A between the two taxanes. Copyright © 2012 John Wiley & Sons, Ltd.     

Influence of vasomodulators and tumor transplantation on the disposition of 5‐fluorouracil after application to the liver surface in rats

This study investigated the effect of epinephrine (a vasoconstrictor) and hydralazine (a vasodilator) on the hepatic disposition of 5‐fluorouracil (5‐FU) after application to the surface of the liver in rats. Normal livers were compared with a Walker 256 carcinoma cell tumor model. A cylindrical diffusion cell was attached to the liver surface. 5‐Fluorouracil was added into the diffusion cell in combination with vasomodulators or after pretreatment with epinephrine. After selected treatment times, the 5‐FU concentrations were assayed at three sites in the excised livers. The 5‐FU concentration in the region under the cell attachment site (site 1) was significantly higher after concomitant application of 5‐FU and epinephrine, compared with 5‐FU alone, and increased in an epinephrine dose‐dependent manner. On the other hand, preferential distribution of 5‐FU at site 1 was not seen when applied in combination with hydralazine. After 10 min of epinephrine pretreatment, the concentration of 5‐FU at site 1 was approximately two times higher than that for the control. Furthermore, the 5‐FU concentration at site 1 of the tumor model was greatly increased compared with the normal liver. These results suggest that application of epinephrine to the liver surface might enhance the accumulation of 5‐FU at the desired target site.     

Attenuation of the LPS‐induced,ERK‐mediated upregulation of fibrosis‐related factors FGF‐2, uPA,MMP‐2, and MMP‐9 by Carthamus tinctorius L in cardiomyoblasts

Severe and potentially fatal hypotension and cardiac contractile dysfunction are common symptoms in patients with sepsis. LPS was previously found to dramatically upregulate expression of fibrosis‐related factors FGF‐2, uPA, MMP‐2, and MMP‐9 in primary cardiac fibroblasts. MMPs are capable of denaturing and degrading fibrillar collagens and other components of the extracellular matrix (ECM). Studies have shown that dysregulation of expression of MMPs is associated with development of myocardial extracellular matrix remodeling and cardiac fibrosis, which contribute to progression of heart failure. In this study, H9c2 cells and cardiac fibroblasts were divided into five treatment groups: control, LPS (1 μg/mL) and three concentrations of FC_EtOH (Carthami Flos ethanolic extract) (31.25, 62.5, and 125 μg/mL). Phosphorylation of ERK‐1/2 was observed to be rapidly induced upon treatment with LPS. In contrast, it was significantly suppressed by the administration of FC_EtOH (125 μg/mL). Effects of FC_EtOH on LPS‐induced MMP‐2 and MMP‐9 expression in H9c2 cells occurred directly through ERK1/2 were determined. H9c2 cells were therefore pretreated with EGF‐R to activate ERK pathway. Both protein levels of MMP‐2 and MMP‐9 and immunefluorescent signals of MMP‐9 were significantly enhanced by EGFR. In contrast, MMP‐2 and MMP‐9 were significantly reduced after FC_EtOH administration. Based on these findings, the authors concluded that FC_EtOH elicits a protective effect against LPS‐induced cardio‐fibrosis through the ERK1/2 pathway. Carthamus tinctorius L may potentially serve as a cardio‐protective agent against LPS‐ induced cardiac fibrosis. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 754–763, 2017.     

Effects of acute renal failure induced by uranyl nitrate on the pharmacokinetics of liquiritigenin and its two glucuronides, M1 and M2, in rats

Objectives Liver disease and acute renal failure (ARF) are closely associated. The pharmacokinetics of liquiritigenin (LQ), a candidate therapy for inflammatory liver disease, and its metabolites M1 and M2 were evaluated in rats with ARF induced by uranyl nitrate (U‐ARF rats). Methods LQ was administered intravenously (20 mg/kg) or orally (50 mg/kg) in U‐ARF and control rats, and uridine diphosphate‐glucuronosyltransferases (UGT) activity and uridine 5′‐diphosphoglucuronic acid (UDPGA) concentrations were determined in the liver and intestine. Key findings After intravenous LQ administration, U‐ARF rats displayed significantly slower LQ renal clearance but no significant changes in the LQ area under the plasma concentration–time curve (AUC) compared with controls. This was because of similar hepatic UGT activity and UDPGA levels between two groups, which resulted in comparable non‐renal clearance, as well as the limited contribution of LQ renal clearance to total LQ clearance. However, the AUC and AUC_M/AUC_LQ ratios of M1 and M2 were significantly increased in U‐ARF rats because of decreased urinary excretion of M1 and M2. Similar results were observed following oral administration because of the comparable LQ intestinal metabolism in both groups and decreased urinary excretion of M1 and M2 in U‐ARF rats. Conclusions U‐ARF rats displayed decreased urinary excretion of LQ glucuronides, resulting in significantly greater AUC and metabolite ratios of M1 and M2 following LQ administration.     

177Lu‐5‐Fluorouracil a potential theranostic radiopharmaceutical: radiosynthesis,quality control,biodistribution, and scintigraphy

The aim of this study is to develop ¹⁷⁷Lu‐5‐Flourouracil as a potential cancer therapeutic radiopharmaceutical. 5‐Flourouracil (5‐FU) is widely accepted as an anticancer drug of broad spectrum fame. The labeling of 5‐FU was carried out at different set of experimental conditions using high specific activity of ¹⁷⁷LuCl₃. The optimum conditions for maximum radiochemical yield was set: 5‐FU (5 mg), ¹⁷⁷LuCl₃ (185 MBq), diethylenetriaminepentaacetic acid (10 µg), reaction volume (2 mL), pH (5.5), temperature (80°C), and reaction time (20 min). The radiochemical labeling was assessed with Whatman No. 2 paper, instant thin layer chromatographic, and radio‐HPLC, which revealed >94% labeling results with sufficient stability up to 6 h. Serum stability study also showed ¹⁷⁷Lu‐5‐FU promising stability. Biodistribution study in normal rats and rabbits showed liver, stomach, kidney, and heart as area of increased tracer accumulation just after injection, which decreased to 1.4%, 0.4%, 0.2%, and 0.39% ID/g, respectively, after 72 h. Glomerular filtration rate and cytotoxicity study results of ¹⁷⁷Lu‐5‐FU showed it had no adverse effect on renal function and nontoxic to blood cells. The promising characteristics of ¹⁷⁷Lu‐5‐FU, that is, clever elimination from kidney and nontoxic nature toward blood cells make it the radiopharmaceutical for further testing in patients for therapeutic purposes.     

Faster clearance of mirodenafil in rats with acute renal failure induced by uranyl nitrate: contribution of increased protein expression of hepatic CYP3A1 and intestinal CYP1A1 and 3A1/2

Objectives It has been reported that mirodenafil is primarily metabolized via hepatic cytochrome P450 (CYP) 1A1/2, 2B1/2, 2D1 and 3A1/2 in rats. It has also been reported that the protein expression of hepatic CYP3A1 and intestinal CYP1A1 and 3A1/2 increases and that of hepatic CYP2D1 decreases in rats with acute renal failure induced by uranyl nitrate (U‐ARF rats). Thus, the pharmacokinetics of mirodenafil were studied in control and U‐ARF rats. Methods The pharmacokinetic parameters of mirodenafil and SK3541 (a metabolite of mirodenafil) were compared after the intravenous and oral administration of mirodenafil at a dose of 20 mg/kg to U‐ARF and control rats. Key findings After interavenous administration of mirodenafil to U‐ARF rats, the total area under the concentration–time curve (AUC) of mirodenafil was significantly smaller (36.5% decrease) than controls, possibly due to the significantly faster non‐renal clearance (66.1% increase; because of increase in the protein expression of hepatic CYP3A1) than controls. After the oral administration of mirodenafil to U‐ARF rats, the AUC of mirodenafil was also significantly smaller (47.8% decrease) due to the increase in the protein expression of hepatic CYP3A1 and intestinal CYP1A1 and 3A1/2 compared with controls. Conclusions After both intravenous and oral administration of mirodenafil to U‐ARF rats, the AUC_SK3541/AUC_mirodenafil ratios were comparable with that in controls and this could be due to further metabolism of SK3541 in rats.     

Cardioprotective effect of matrine on isoproterenol‐induced cardiotoxicity in rats

Objectives This study was designed to explore the effect and mechanism of matrine, an active component of Chinese traditional medicine, on isoproterenol‐induced acute cardiotoxicity in rats. Methods Acute myocardial injury was induced in rats by daily subcutaneous injection of isoproterenol (85 mg/kg) for two days. Haemodynamic and biochemical parameters were measured and histopathological examination was performed. Key findings Chronic oral administration of matrine (50, 100 or 200 mg/kg per day for 10 days) significantly reduced the release of lactic dehydrogenase, glutamic oxaloacetic transaminase and creatine kinase after isoproterenol‐induced myocardial ischaemic injury, improved the left ventricular (LV) dysfunction, including increased LV systolic pressure (LVSP), maximum rate of developed LV pressure (LV dP/dt_max) and minimum rate of developed LV pressure (LV dP/dt_min), increased the activity of superoxide dismutase, catalase and glutathione peroxidase, and also decreased the content of the lipid peroxidation product malondialdehyde in plasma and myocardial tissues in rats. Acute oral administration of matrine at a dose of 100 or 200 mg/kg for two days also had a cardioprotective effect on this rat model. The protective role of matrine on isoproterenol‐induced myocardial damage was further confirmed by histopathological examination. There were no significant changes in heart rate and blood pressure in all experimental groups. Conclusions Our results suggest that matrine has a significant cardioprotection against isoproterenol‐induced cardiotoxicity through its antioxidant property.