Inhibitor of P-glycoprotein-mediated drug transport by curcumin in broiler chickens.

OBJECTIVE: To investigate the role of curcumin in the regulation of P-glycoprotein (P-gp) and its influence on the pharmacokinetics of P-gp substrates. SAMPLE: 39 broiler chicken and chicken embryonic primary hepatocytes. METHODS: Chicken embryonic primary hepatocytes were treated with curcumin, after which cell viability, P-gp expression, and transport were assessed. Broiler chickens were pretreated with curcumin, after which P-gp expression and the pharmacokinetic behavior of orally administered sulfadiazine (a substrate of P-gp) were measured. RESULTS: The preliminary results showed that the viability of chicken embryonic primary hepatocytes was enhanced by pretreatment with 40, 60, and 100 µM curcumin. Curcumin inhibits the expression and transport of P-gp. In vivo experiments showed that curcumin decreased the expression of P-gp in the broiler chicken liver, kidney, and small intestine. Pretreatment with curcumin changed the pharmacokinetic behavior of orally administered sulfadiazine by increasing the area under the curve (47.36 vs 70.35 h·mg/L, P < .01) and peak concentration (10.1 vs 14.53 µg/mL, P < .01). CLINICAL RELEVANCE: Curcumin inhibited the expression and efflux of chicken P-gp, thereby improving the oral bioavailability of P-gp substrate drugs. These findings provide a rationale for exploiting herbal-drug interactions in veterinary practice to improve the absorption of drugs.

Chicken xenobiotic receptor upregulates the BCRP/ABCG2 transporter.

The transporter breast cancer resistance protein (BCRP, encoded by ABCG2) influences the bioavailability and elimination of numerous substrate drugs during clinical therapy. The xenobiotic-sensing nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) reportedly regulate functional expression of BCRP in mammalian species. However, it is unknown whether chicken xenobiotic receptor (CXR) regulates the expression and activity of BCRP. This study aimed to investigate the role of CXR in regulation of BCRP in chicken using in vitro and in vivo models. CXR was expressed in the main drug-metabolizing tissues of chickens, and its expression correlated well with that of the prototypical target genes CYP2H1 and ABCG2. BCRP expression was upregulated, and transporter activity was increased, in chicken primary hepatocytes exposed to the CXR agonist metyrapone. Using RNA interference and ectopic expression techniques to manipulate the cellular CXR status, we confirmed that ABCG2 gene regulation depended on CXR. In vivo experiments showed that metyrapone induced BCRP in the liver, kidney, duodenum, and jejunum of chickens. Coadministration of metyrapone significantly changed the pharmacokinetic behavior of orally administered florfenicol (substrate of chicken BCRP), with a lower Cmax (4.62 vs. 7.35 µg/mL, P < 0.01) and AUC0-t (15.83 vs. 24.18 h·mg/L, P < 0.01) as well as a higher Tmax (0.96 vs. 0.79 h, P < 0.05) and Cl/F (0.13 vs. 0.08 L/h/kg, P < 0.05). Together, our data suggest that CXR is involved in regulation of BCRP, and consequently, coadministration of a CXR agonist can affect the pharmacokinetic behavior of an orally administered BCRP substrate.

Ivermectin induces chicken BCRP/ABCG2 expression and function: Involvement of CXR signaling pathway and mRNA stabilization.

Ivermectin is a macrocyclic lactone antiparasitic drug widely used in human and veterinary medicine. Previous studies indicated that ivermectin could interact with P-glycoprotein, being a good inducer and substrate; however, it is unknown whether ivermectin affects BCRP of chicken. In this study, we found that ivermectin distinctly affected the expression of BCRP in a time- and concentration-dependent up-regulatory way in chicken primary hepatocytes. Subsequent series of experiments showed that the BCRP induction is related with the increase of CXR expression and, promoting CXR translocations to the nucleus and enhancing the stability of Abcg2 mRNA at the post-transcriptional level by ivermectin. Furthermore, we observed that ivermectin also enhanced the stability of Abcg2 mRNA at the post-transcriptional level by Act-D chase assay. We got the similar results by in vivo test that ivermectin-induced BCRP and CXR expression in pharmacologically important tissues, and decreased the apparent permeability coefficient of florfenicol (substrate of chicken BCRP). In conclusion, the results indicated that ivermectin could induce chicken BCRP expression and function through the transcriptional CXR signaling pathway and post-transcriptional mRNA stabilization.

Potential Pharmacokinetic Effect of Chicken Xenobiotic Receptor Activator on Sulfadiazine: Involvement of P-glycoprotein Induction.

Studies on pharmacokinetic drug−drug interactions have highlighted the importance of P-glycoprotein (P-gp) because of its involvement in substrate drug transport. This study aimed to investigate the role of chicken xenobiotic receptor (CXR) in the regulation of P-gp and its influences on pharmacokinetics of P-gp substrate sulfadiazine. ALAS1 and CYP2C45, the prototypical target genes of CXR, were used as a positive indicator for CXR activation in this study. Results show that ABCB1 gene expression was upregulated, and transporter activity was increased when exposed to the CXR activator metyrapone. Using ectopic expression techniques and RNA interference to manipulate the cellular CXR status, we confirmed that ABCB1 gene regulation depends on CXR. In vivo experiments showed that metyrapone induced ABCB1 in the liver, kidney, duodenum, jejunum and ileum of chickens. In addition, metyrapone significantly changed the pharmacokinetic behavior of orally administered sulfadiazine, with a Cmax (8.01 vs. 9.61 µg/mL, p < 0.05) and AUC0-t (31.46 vs. 45.59 h·mg/L, p < 0.01), as well as a higher T1/2λ (2.42 vs.1.67 h, p < 0.05), Cl/F (0.62 vs. 0.43 L/h/kg, p < 0.01) and Vz/F (2.16 vs.1.03 L/kg, p < 0.01). Together, our data suggest that CXR is involved in the regulation of P-gp, and, consequently, the CXR activator can affect, at least in part, the pharmacokinetic behavior of orally administered sulfadiazine.

Broadband Cooperative Spectrum Sensing Based on Distributed Modulated Wideband Converter.

The modulated wideband converter (MWC) is a kind of sub-Nyquist sampling system which is developed from compressed sensing theory. It accomplishes highly accurate broadband sparse signal recovery by multichannel sub-Nyquist sampling sequences. However, when the number of sparse sub-bands becomes large, the amount of sampling channels increases proportionally. Besides, it is very hard to adjust the number of sampling channels when the sparsity changes, because its undersampling board is designed by a given sparsity. Such hardware cost and inconvenience are unacceptable in practical applications. This paper proposes a distributed modulated wideband converter (DMWC) scheme innovatively, which regards one sensor node as one sampling channel and combines MWC technology with a broadband cooperative spectrum sensing network perfectly. Being different from the MWC scheme, DMWC takes phase shift and transmission loss into account in the input terminal, which are unavoidable in practical application. Our scheme is not only able to recover the support of broadband sparse signals quickly and accurately, but also reduces the hardware cost of the single node drastically. Theoretical analysis and numerical simulations show that phase shift has no influence on the recovery of frequency support, but transmission loss degrades the recovery performance to a different extent. Nevertheless, we can increase the amount of cooperative nodes and select satisfactory nodes by a different transmission distance to improve the recovery performance. Furthermore, we can adjust the amount of cooperative nodes flexibly when the sparsity changes. It indicates DMWC is extremely effective in the broadband cooperative spectrum sensing network.

Prediction of radiation induced liver disease using artificial neural networks.

OBJECTIVE: To evaluate the efficiency of predicting radiation induced liver disease (RILD) with an artificial neural network (ANN) model. METHODS AND MATERIALS: From August 2000 to November 2004, a total of 93 primary liver carcinoma (PLC) patients with single lesion and associated with hepatic cirrhosis of Child-Pugh grade A, were treated with hypofractionated three-dimensional conformal radiotherapy (3DCRT). Eight out of 93 patients were diagnosed RILD. Ninety-three patients were randomly divided into two subsets (training set and verification set). In model A, the ratio of patient numbers was 1:1 for training and verification set, and in model B, the ratio was 2:1. RESULTS: The areas under receiver-operating characteristic (ROC) curves were 0.8897 and 0.8831 for model A and B, respectively. Sensitivity, specificity, accuracy, positive prediction value (PPV) and negative prediction value (NPV) were 0.875 (7/8), 0.882 (75/85), 0.882 (82/93), 0.412 (7/17) and 0.987 (75/76) for model A, and 0.750 (6/8), 0.800 (68/85), 0.796 (74/93), 0.261 (6/23) and 0.971 (68/70) for model B. CONCLUSION: ANN was proved high accuracy for prediction of RILD. It could be used together with other models and dosimetric parameters to evaluate hepatic irradiation plans.