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Scavenger receptor BI: A multi-purpose player in cholesterol and steroid metabolism

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World Journal of Gastroenterology 2010年第47期16卷 591-5924页

作者： Menno Hoekstra Theo JC Van Berkel Miranda Van Eck division of biopharmaceutics Leiden/Amsterdam Center for Drug Research Gorlaeus Laboratories

Scavenger receptor class B type Ⅰ (SR-BI) is an important member of the scavenger receptor family of integral membrane glycoproteins. This review highlights studies in SR-BI knockout mice, which concern the role of SR-BI in cholesterol and steroid metabolism. SR-BI in hepatocytes is the sole molecule involved in selective uptake of cholesteryl esters from high-density lipoprotein (HDL). SR-BI plays a physiological role in binding and uptake of native apolipoprotein B (apoB)-containing lipoproteins by hepatocytes, which identif ies SR-BI as a multipurpose player in lipid uptake from the blood circulation into hepatocytes in mice. In adrenocortical cells, SR-BI mediates the selective uptake of HDL-cholesteryl esters, which is eff iciently coupled to the synthesis of glucocorticoids (i.e. corticosterone). SR-BI knockout mice suffer from adrenal glucocorticoid insuff iciency, which suggests that functional SR-BI protein is necessary for optimal adrenal steroidogenesis in mice. SR-BI in macrophages plays a dual role in cholesterol metabolism as it is able to take up cholesterol associated with HDL and apoBcontaining lipoproteins and can possibly facilitate cholesterol efflux to HDL. Absence of SR-BI is associated with thrombocytopenia and altered thrombosis susceptibility, which suggests a novel role for SR-BI in regulating platelet number and function in mice. Transgenic expression of cholesteryl ester transfer protein in humanized SR-BI knockout mice normalizes hepatic delivery of HDL-cholesteryl esters. However, other pathologies associated with SR-BI def iciency, i.e. increased atherosclerosis susceptibility, adrenal glucocorticoid insuffi ciency, and impaired platelet function are not normalized, which suggests an important role for SR-BI in cholesterol and steroid metabolism in man. In conclusion, generation of SR-BI knockout mice has signif icantly contributed to our knowledge of the physiological role of SR-BI. Studies using these mice have identif ied SR-BI as a

关键词： Scavenger receptor class B type Ⅰ Highdensity lipoprotein Cholesterol Lipoprotein metabolism Liver Macrophages Adrenal gland Platelets Steroido- genesis

Rifabutin reduces systemic exposure of an antimalarial drug 97/78 upon co-administration in rats:an in-vivo & in-vitro analysis

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Asian Pacific Journal of Tropical Medicine 2015年第8期8卷 620-625页

作者： Yeshwant Singh Mahendra Kumar Hidau Shio Kumar Singh pharmacokinetics & Metabolism division CSIR-Central Drug Research Institute Academy of Scientific and Innovative Research

Objective: To determine the potential drug-drug interactions between anti-malarial candidate 97/78 and anti-tubercular drug rifabutin in-vivo in rats followed by in-vitro investigation of the underlying mechanisms of drug interaction. Methods: Single oral dose study was conducted in male and female rats at 40 mg/kg and 70 mg/kg for 97/78 and rifabutin respectively. Results: It was reported that rifabutin co-administration altered pharmacokinetics of 97/63(active metabolite of 97/78). A significant decrease was reported in the systemic exposure of 97/63 by a factor of 3-4. The AUC0-last values were(4.03 ± 0.60) and(5.44 ± 1.15) μg·h·m L-1 upon 97/78 administration alone, while the values were decreased to(1.13 ± 0.10) and(1.23 ± 1.13) μg·h·m L-1 upon rifabutin co-administration in male and female rats respectively. Statistically significant differences were also reported in Cmax and Tmax values upon rifabutin co-administration. In-vitro drug metabolism study in rat liver microsomes has shown that the metabolism of 97/63 was increased by 10%-12% upon rifabutin co-incubation. The extent of plasma protein binding of 97/63 was found to be decreased from 54%-55% to 6%-8% upon rifabutin addition. Conclusions: It was concluded that rifabutin co-administration altered PK parameters of 97/63 in SD rats. However, no intersex influences were reported in the interaction pattern. The results obtained in the in-vivo study were well correlated with the invitro findings and can further be applied to explore other aspects of potential drug interactions between these two drugs.

关键词： Accumulation Relative bioavailability Sex effect pharmacokinetics

Role of rat liver cytochrome P450 3A and 2D in metabolism of imrecoxib

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Acta Pharmacologica Sinica 2006年第3期27卷 372-380页

作者： Hai-yan XU~2 Zhi-yong XIE~2 Peng ZHANG~2 Jin SUN~3 Feng-ming CHU~4 Zong-ru GUO~4 Da-fang ZHONG~(2,5) ~2Laboratory of Drug Metabolism and pharmacokinetics ~3Department of biopharmaceutics,Shenyang Pharmaceutical University,Shenyang 110016,China ~4Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China Laboratory of Drug Metabolism and pharmacokinetics Shenyang Pharmaceutical University Shenyang China Department of biopharmaceutics Shenyang Pharmaceutical University Shenyang China Institute of Materia Medica Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China

Aim:To investigate the in vitro metabolism of imrecoxib in rat liver microsomesand to identify the cytochrome P450(CYP)forms involved in its ***:Liver microsomes of Wistar rats were prepared using an *** in vitro metabolism of imrecoxib was studied by incubation with rat *** characterize the CYP forms involved in the 4'-methyl hydroxyla-tion of imrecoxib,the effects of typical CYP inducers(such as dexamethasone,isoniazid and β-naphthoflavone)and of CYP inhibitors(such as ketoconazole,quinine,α-naphthoflavone,methylpyrazole,and cimetidine)on the formation rateof 4'-hydroxymethyl imrecoxib were ***:Imrecoxib was me-tabolized to 3 metabolites by rat liver microsomes:4'-hydroxymethyl imrecoxib(M4),4'-hydroxymethyl-5-hydoxyl imrecoxib(M3),and 4'-hydroxymethyl-5-car-bonyl imrecoxib(M5).Over the imrecoxib concentration range studied(5-600μmol/L),the rate of 4'-methyl hydroxylation conformed to monophasic Michaelis-Menten *** significantly induced the formation of *** markedly lowered the metabolic rate of imrecoxib in a concentra-tion-dependent ***,a significant inhibitory effect of quinine onthe formation of M4 was observed in microsomes obtained from control rats,isoniazid-induced rats,and β-naphthofiavone-induced *** contrast,α-naphthoflavone,cimetidine,and methylpyrazole had no inhibitory effects on thismetabolic ***:Imrecoxib is metabolized via 4'-methyl hydroxy-lation in rat liver microsomes,The reaction is mainly catalyzed by CYP ***2D also played a role in control rats,in isoniazid-induced rats and in β-naphthoflavone-induced rats.

关键词： imrecoxib cytochrome P450 metabolism liver microsomes

Update on the reciprocal interference between immunosuppressive therapy and gut microbiota after kidney transplantation

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World Journal of Transplantation 2024年第1期14卷 72-83页

作者： Maurizio Salvadori Giuseppina Rosso Department of Renal Transplantation Careggi University HospitalFlorence 50139TuscanyItaly division of Nephrology San Giovanni di Dio HospitalFlorence 50143ToscanaItaly

Gut microbiota is often modified after kidney *** principally happens in the first period after *** and,most of all,immunosuppressive drugs are the main *** relationship between immunosuppressive drugs and the gut microbiota is *** one side immunosuppressive drugs modify the gut microbiota,often generating dysbiosis;from the other side microbiota may interfere with the immunosuppressant pharmacokinetics,producing products more or less active with respect to the original *** phenomena have influence over the graft outcomes and clinical consequences as rejections,infections,diarrhea may be caused by the dysbiotic ***,calcineurin inhibitors such as tacrolimus and cyclosporine,mycophenolate mofetil and mTOR inhibitors are the immunosuppressive drugs whose effect on the gut microbiota is better *** contrast is well known how the gut microbiota may interfere with glucocorticoids,which may be transformed into *** may be transformed by microbiota into a product called M1 that is 15-fold less active with respect to *** pro-drug mycophenolate mofetil is normally transformed in mycophenolic acid that according the presence or not of microbes producing the enzyme glucuronidase,may be transformed into the inactive product.

关键词： Immunosuppressive therapy Kidney transplantation Gut microbiota Dysbiosis Pathobionts Graft outcomes

Protective effects of ursodeoxycholic acid on chenodeoxycholic acid-induced liver injury in hamsters

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World Journal of Gastroenterology 2007年第37期13卷 5003-5008页

作者： Tomomichi Iwaki Kaoru Ishizaki Shuji Kinoshita Hideki Tanaka Atsushi Fukunari Makoto Tsurufuji Teruaki Imada Research Laboratory Ⅲ (Immunology) Pharmaceuticals Research Division Mitsubishi Pharma Corporation Yokohama Japan pharmacokinetics Laboratory Pharmaceuticals Research Division Mitsubishi Pharma Corporation Chiba Japan Discovery Technology Laboratory Pharmaceuticals Research Division Mitsubishi Pharma Corporation Yokohama Japan

AIM： TO investigate the effects of ursodeoxycholic acid （UDCA） on chenodeoxycholic acid （CDCA）-induced liver injury in hamsters, and to elucidate a correlation between liver injury and bile acid profiles in the liver.METHODS： Liver injury was induced in hamsters by administration of 0.5% （w/w） CDCA in their feed for 7 d. UDCA （50 mg/kg and 150 mg/kg） was administered for the last 3 d of the experiment.RESULTS： At the end of the experiment, serum alanine aminotransferase （ALl） increased more than 10 times and the presence of liver injury was confirmed histologically. Marked increase in bile acids was observed in the liver. The amount of total bile acids increased approximately three-fold and was accompanied by the increase in hydrophobic bile acids, CDCA and lithocholic acid （LCA）. UDCA （50 mg/kg and 150 mg/kg） improved liver histology, with a significant decrease （679.3 ±77.5 U/L vs 333.6 ± 50.4 U/L and 254.3 ±35.5 U/ L, respectively, P 〈 0.01） in serum ALT level. UDCA decreased the concentrations of the hydrophobic bile acids, and as a result, a decrease in the total bile acid level in the liver was achieved.CONCLUSION： The results show that UDCA improves oral CDCA-induced liver damage in hamsters. The protective effects of UDCA appear to result from a decrease in the concentration of hydrophobic bile acids, CDCA and LCA, which accumulate and show the cytotoxicity in the liver.

关键词： Chenodeoxycholic acid Hamster Liver bileacids Ursodeoxycholic acid

Evaluation of the Mrp2-mediated flavonoid-drug interaction potential of quercetin in rats and in vitro models

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Asian Journal of Pharmaceutical Sciences 2019年第6期14卷 621-630页

作者： Ju-Hee Oh Joo Hyun Lee Young-Joo Lee division of biopharmaceutics College of PharmacyKyung Hee UniversitySeoul 02447Republic of Korea Department of Life and Nanopharmaceutical Sciences College of PharmacyKyung Hee UniversitySeoul 02447Republic of Korea

Quercetin is a biologically active flavonoid that has been used as a popular health *** is reported that quercetin may cause flavonoid-drug interaction mediated by P-glycoprotein,the most predominant efflux *** this study,we comprehensively evaluated the potential of the pharmacokinetic interaction of quercetin mediated by multidrug resistance-associated protein 2(MRP2),another major efflux ***2-transfected MDCKII cells and LS174T cells were used to evaluate the potential inhibition and induction of MRP2 by quercetin in *** evaluate the induction effect of quercetin on Mrp2 in vivo,Mrp2 mRNA expression in rat liver,kidney,and small intestinal tissues was determined after the oral administration of quercetin(50,100,or 250 mg/kg)for seven ***2-mediated interaction potential was also evaluated by the pharmacokinetic study of phenolsulfonphthalein in rats after single or multiple doses of ***,the effect of quercetin on absorption of docetaxel,a P-glycoprotein and CYP3A4 substrate,was also *** inhibited the function of MRP2 at 10μM and induced the mRNA expression of MRP2 at 50μM in ***,at 100 mg/kg,quercetin markedly increased Mrp2 expression in the small intestine of ***,there was no significant change in phenolsulfonphthalein pharmacokinetics due to single-(50,100,or 250 mg/kg)or multiple-dose(50,100,or 250 mg/kg for seven days)quercetin *** contrast,a significant interaction caused by quercetin(100 mg/kg)was observed in the absorption of *** results suggested that although quercetin modulates the function and expression of MRP2 in vitro,it may have a low potential of Mrp2-mediated interaction and present negligible safety concerns related to the interaction.

关键词： Quercetin P-glycoprotein Multidrug resistance-associated protein 2 pharmacokinetics Flavonoid-drug interaction

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Modularly engineered prodrug-nanoassemblies for cancer therapy:Nonpharmacological moiety dominating delivery fates

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Nano Research 2023年第1期16卷 980-990页

作者： Yuequan Wang Qian Qiu Rui Liao Xinhui Wang Ziran Zhou Xuanbo Zhang Haotian Zhang Zhonggui He Shenwu Zhang Cong Luo Jin Sun Department of Pharmaceutics Wuya College of InnovationShenyang Pharmaceutical UniversityShenyang 110016China School of Life Science and biopharmaceutics Shenyang Pharmaceutical UniversityShenyang 110016China

Self-engineered small-molecule prodrug-nanoassemblies have emerged as promising nanomedicines for cancer *** design of prodrug molecules is crucial to guarantee the favorable assembly stability,tumor-specific prodrug activation,and satisfactory antitumor ***,too much attention has been paid to the pharmacophores and chemical linkages in prodrug molecules while neglects the vital roles of nonpharmacological ***,we found that iso-carbon fatty acids with different number,position,and cis-trans configuration of double bonds dramatically affect the nanoassembly feature and drug delivery fates of thioether-linked paclitaxel ***,the number and cis-trans configuration of double bonds in fatty acid moieties not only dominate the self-assembly ability and colloidal stability of prodrugs,but also exert significant influences on the pharmacokinetics,prodrug activation,and antitumor activity of ***,oleic acid with one cis double bond stands out as the optimal nonpharmacological moiety for thioether-linked paclitaxel *** study elucidates the crucial roles of nonpharmacological moieties in prodrugs,and provides new insights into the modular design of prodrug-based nanomedicines for cancer therapy.

关键词： small-molecule prodrug paclitaxel self-assembly ability nonpharmacological moiety modular engineering delivery fate

Emerging roles of the intestine in control of cholesterol metabolism

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World Journal of Gastroenterology 2006年第40期12卷 6429-6439页

作者： Janine K Kruit Albert K Groen Theo J van Berkel Folkert Kuipers Department of Pediatrics Center for Liver Digestive and Metabolic Diseases University Medical Center Groningen Groningen The Netherlands Department of Experimental Hepatology Academic Medical Center Amsterdam The Netherlands division of biopharmaceutics Leiden/Amsterdam Center for Drug Research Leiden University Leiden The Netherlands

The liver is considered the major “control center” for maintenance of whole body cholesterol homeostasis. This organ is the main site for de novo cholesterol synthesis, clears cholesterol-containing chylomicron remnants and low density lipoprotein particles from plasma and is the major contributor to high density lipoprotein (HDL; good cholesterol) formation. The liver has a central position in the classical definition of the reverse cholesterol transport pathway by taking up periphery-derived cholesterol from lipoprotein particles followed by conversion into bile acids or its direct secretion into bile for eventual removal via the feces. During the past couple of years, however, an additional important role of the intestine in maintenance of cholesterol homeostasis and regulation of plasma cholesterol levels has become apparent. Firstly, molecular mechanisms of cholesterol absorption have been elucidated and novel pharmacological compounds have been identified that interfere with the process and positively impact plasma cholesterol levels. Secondly, it is now evident that the intestine itself contributes to fecal neutral sterol loss as a cholesterol-secreting organ. Finally, very recent work has unequivocally demonstrated that the intestine contributes significantly to plasma HDL cholesterol levels. Thus, the intestine is a potential target for novel anti-atherosclerotic treatment strategies that, in addition to interference with cholesterol absorption, modulate direct cholesterol excretion and plasma HDL cholesterol levels.

关键词： Cholesterol metabolism Intestine High density lipoprotein Cholesterol absorption Reverse cholesterol transport

Genomic Diversity and Evolution of Bacillus subtilis

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Biomedical and Environmental Sciences 2015年第8期28卷 620-625页

作者： YU Gang WANG Xun Cheng TIAN Wang Hong SHI Ji Chun WANG Bin YE Qiang DONG Si Guo ZENG Ming WANG Jun Zhi The State Key Laboratory of Cancer Biology Department of Biopharmaceutics School of Pharmacy Fourth Military Medical University division of Enteric Bacterial Vaccines National Institutes for Food and Drug Control Tsinghua-Peking Joint Center for Life Sciences School of Life Sciences Tsinghua university

Bacillus subtilis is the focus of both academic and industrial *** studies have reported a number of sequence variations in different *** *** uncover the genetic variation and evolutionary pressure in *** strains,we performed whole genome sequencing of two *** isolates,KM and *** genomic analyses of these two strains with other *** strains identified high

关键词： gene SNPs

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