Co-reporter:Ying Li;Ji Zhang;Ping Xu;Binbin Sun;Zeyu Zhong;Can Liu;Zhaoli Ling;Yang Chen;Nan Shu;Kaijing Zhao;Li Liu;Xiaodong Liu
Journal of Neurochemistry 2016 Volume 138( Issue 2) pp:282-294
Publication Date(Web):
DOI:10.1111/jnc.13666
Co-reporter:Xiange Tang, Xinyu Di, Zeyu Zhong, Qiushi Xie, Yang Chen, Fan Wang, Zhaoli Ling, Ping Xu, Kaijing Zhao, Zhongjian Wang, Li Liu, Xiaodong Liu
Journal of Pharmaceutical and Biomedical Analysis 2016 Volume 128() pp:98-105
Publication Date(Web):5 September 2016
DOI:10.1016/j.jpba.2016.05.024
•First identification of metabolism profile of l-corydalmine (l-CDL) in vitro.•Primary enzymes and their contributions to main metabolisms formation of l-CDL.•Comparison of kinetics in human liver microsomes and recombinant P450 enzymes.l-Corydalmine (l-CDL) was under development as an oral analgesic agent, exhibiting potent analgesic activity in preclinical models. The objective of this study was to compare metabolic profiles of l-CDL in liver microsomes from mouse, rat, monkey, dog and human. Six metabolites (M1–M6) were identified using LC-Q/TOF in liver microsomes from the five species. The metabolism of l-CDL included O-demethylation (M1–3) and hydroxylation (M4–6). The desmethyl metabolites were the major ones among the five species, which accounted for more than 84%. Data from chemical inhibition in human liver microsomes (HLM) and human recombinant CYP450s demonstrated that CYP2D6 exhibited strong catalytic activity towards M1 and M2 formations, while CYP2C9 and CYP2C19 also catalyzed M2 formation. Formations of M3 and hydroxyl metabolites (M4 and M5) were mainly catalyzed by CYP3A4. Further studies showed that M1 and M2 were main metabolites in HLM. The kinetics of M1 and M2 formations in HLM and recombinant CYP450s were also investigated. The results showed that M1 and M2 formations in HLM and recombinant CYP2D6 characterized biphasic kinetics, whereas sigmoid Vmax model was better used to fit M2 formation by recombinant CYP2C9 and CYP2C19. The contributions of CYP2D6 to M1 and M2 formations in HLM were estimated to be 75.3% and 50.7%, respectively. However, the contributions of CYP2C9 and CYP2C19 to M2 formation were only 5.0% and 4.1%, respectively. All these data indicated that M1 and M2 were main metabolites in HLM, and CYP2D6 was the primary enzyme responsible for their formations.
Co-reporter:Hai-fang Guo;Can Liu;Jia Li;Zeyu Zhong;Li Liu;Xiao-dong Liu
Clinical Pharmacokinetics 2015 Volume 54( Issue 2) pp:179-193
Publication Date(Web):2015/02/01
DOI:10.1007/s40262-014-0192-8
Accumulating evidence has shown that diabetes mellitus may affect the pharmacokinetics of some drugs, leading to alteration of pharmacodynamics and/or toxic effects. The aim of this study was to develop a novel physiologically based pharmacokinetic (PBPK) model for predicting drug pharmacokinetics in patients with type 2 diabetes mellitus quantitatively.Contributions of diabetes-induced alteration of physiological parameters including gastric emptying rates, intestinal transit time, drug metabolism in liver and kidney functions were incorporated into the model. Plasma concentration–time profiles and pharmacokinetic parameters of seven drugs (antipyrine, nisoldipine, repaglinide, glibenclamide, glimepiride, chlorzoxazone, and metformin) in non-diabetic and diabetic patients were predicted using the developed model. The PBPK model coupled with a Monte-Carlo simulation was also used to predict the means and variability of pharmacokinetic parameters.The predicted area under the plasma concentration–time curve (AUC) and maximum (peak) concentration (Cmax) were reasonably consistent (<2-fold errors) with the reported values. Sensitivity analysis showed that gut transit time, hepatic enzyme activity, and renal function affected the pharmacokinetic characteristics of these drugs. Shortened gut transit time only decreased the AUC of controlled-released drugs and drugs with low absorption rates. Impairment of renal function markedly altered pharmacokinetics of drugs mainly eliminated via the kidneys.All of these results indicate that the developed PBPK model can quantitatively predict pharmacokinetic alterations induced by diabetes.
Co-reporter:Ji Zhang;Mian Zhang;Binbin Sun;Ying Li;Ping Xu;Can Liu;Li Liu;Xiaodong Liu
Journal of Neurochemistry 2014 Volume 131( Issue 6) pp:791-802
Publication Date(Web):
DOI:10.1111/jnc.12944
Co-reporter:Yang Yang, Yang Chen, Ze-Yu Zhong, Ji Zhang, Feng Li, Ling-Ling Jia, Li Liu, Xiong Zhu, Xiao-Dong Liu
Journal of Pharmaceutical and Biomedical Analysis 2014 Volume 88() pp:410-415
Publication Date(Web):25 January 2014
DOI:10.1016/j.jpba.2013.09.027
•A LC–MS/MS method was first developed and validated for the determination of deoxypodophyllotoxin in rat plasma.•Good peak shape and sensitivity with acceptable matrix effect could be obtained.•It is the first pharmacokinetic study of the intravenous administration of DPT in rats.•The pharmacokinetic parameters were obtained through two-compartment intravenous models analysis.A rapid and sensitive liquid chromatography/tandem mass spectrometry method was developed and validated for the quantification of deoxypodophyllotoxin (DPT) concentration in rat plasma with diazepam as internal standard (IS). DPT and IS were extracted with ethyl acetate, and the chromatographic separation was accomplished by using a Waters Symmetry C18 analytical column (2.1 mm × 150 mm, 5 μm) with a mobile phase consisting of acetonitrile and deionized water (70:30, v:v) containing 0.1% formic acid at a flow rate of 0.2 mL/min. Multiple Reaction Monitoring (MRM), using electrospray ionization in positive ion mode, was employed to quantitatively detect DPT and IS. The monitored transitions were set at m/z 399.05–231.00 and m/z 285.00–154.00 for DPT and IS, respectively. The calibration curve was linear over the concentration range of 7.8–1000 ng/mL (R2 ≥ 0.9999). The intra- and inter-day precision values were less than 7%. Similarly, the mean intra- and inter-day accuracy were found to be within −2.8% to 1.9% of the interval, with all samples locating within general assay acceptability criteria for QC samples according to FDA guidelines. This method was further and successfully applied in the pharmacokinetics study of DPT in rat.
Co-reporter:Haifang Guo;Can Liu;Jia Li;Mian Zhang;Mengyue Hu;Ping Xu;Li Liu;Xiaodong Liu
Journal of Pharmaceutical Sciences 2013 Volume 102( Issue 8) pp:2819-2836
Publication Date(Web):
DOI:10.1002/jps.23613
Abstract
Cytochrome P450 (CYP) 3A induction-mediated drug–drug interaction (DDI) is one of the major concerns in drug development and clinical practice. The aim of the present study was to develop a novel mechanistic physiologically based pharmacokinetic (PBPK)-enzyme turnover model involving both intestinal and hepatic CYP3A induction to quantitatively predict magnitude of CYP3A induction-mediated DDIs from in vitro data. The contribution of intestinal P-glycoprotein (P-gp) was also incorporated into the PBPK model. First, the pharmacokinetic profiles of three inducers and 14 CYP3A substrates were predicted successfully using the developed model, with the predicted area under the plasma concentration-time curve (AUC) [area under the plasma concentration-time curve] and the peak concentration (Cmax) [the peak concentration] in accordance with reported values. The model was further applied to predict DDIs between the three inducers and 14 CYP3A substrates. Results showed that predicted AUC and Cmax ratios in the presence and absence of inducer were within twofold of observed values for 17 (74%) of the 23 DDI studies, and for 14 (82%) of the 17 DDI studies, respectively. All the results gave us a conclusion that the developed mechanistic PBPK-enzyme turnover model showed great advantages on quantitative prediction of CYP3A induction-mediated DDIs. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2819–2836, 2013
Co-reporter:Y. Liu;G. Wang;L. Xie;S. Lu;D. Wang;L. Liu;Xiao-dong Liu
Journal of Endocrinological Investigation 2011 Volume 34( Issue 1) pp:26-31
Publication Date(Web):2011/01/01
DOI:10.1007/BF03346691
Enzymes that degrade the amyloid β-peptide (Aβ) are important regulators of cerebral Aβ levels. High level of Aβ was found in the brain of diabetic patients and diabetic animals. Aim of the study was to investigate whether activities of Aβ-degrading enzymes neprilysin (NEP), endothelin-converting enzyme 1 (ECE-1) and insulin-degrading enzyme (IDE) were impaired in the brain of diabetic rats. Diabetes was induced in rats by ip administration of 65 mg/kg streptozotocin. The temporal cortex and hippocampus were obtained for activity and mRNA level assays of the three enzymes on the 35th day after induction. ECE-1 activity was significantly decreased both in the hippocampus and cortex of diabetic rats, while for IDE significantly lower activity occurred only in the cortex. NEP activity was slightly decreased in both brain regions. The hippocampus of diabetic rats showed significant decrease in mRNA levels of NEP and ECE-1 and moderate increase in IDE mRNA level. The cortex of diabetic rats showed slight decrease in mRNA levels of the three enzymes. The results indicated that the three Aβ-degrading enzymes were damaged to different extents in the brain of diabetic rats, and impairment of ECE-1 and IDE partly contributed to the elevated Aβ(1–40) levels in brain of diabetic rats.
Co-reporter:Dan Yao;Zhi-Hong Yang;Li Liu;Jia Li
Naunyn-Schmiedeberg's Archives of Pharmacology 2011 Volume 383( Issue 4) pp:393-402
Publication Date(Web):2011 April
DOI:10.1007/s00210-011-0609-y
The aim of the study was to report a concentration-dependently biphasic effect of verapamil (VER) on the transport of phenobarbital (PB) across the blood–brain barrier (BBB) in vitro and in vivo. The uptake of PB by rat brain microvessel endothelial cells (rBMECs) and transport of PB across the rBMEC monolayer from apical to basolateral and basolateral to apical were evaluated in the presence of VER. The effect of VER on PB pharmacological activity on the central nervous system (CNS) and brain distribution of PB in mice were further investigated. The results showed that VER regulated the uptake of PB by rBMECs in a concentration-dependently biphasic manner. The uptake of PB by rBMECs was decreased by low concentrations of VER (1–25 μΜ), but increased by high concentrations of VER (50–300 μM). The biphasic regulation was also observed in transport experiment. In vivo studies showed that VER altered the pharmacological effect of PB on CNS and brain concentration of PB in a biphasic manner. In contrast to low doses of VER (0.125–0.5 mg/kg) that shortened the duration time of PB-induced loss of the righting reflex, high doses of VER (2–4 mg/kg) prolonged the duration time. Further study demonstrated that brain concentration of PB was decreased by 0.125 mg/kg VER, but increased by 2 mg/kg VER. The concentration-dependently biphasic regulation was also confirmed in the uptake of rhodamine 123 by rBMECs. Our results suggested that VER may regulate the transport of PB across BBB in a concentration-dependently biphasic manner and the biphasic regulation may be involved in P-gp function.
Co-reporter:Xinyue Jing;Xiang Liu;Tao Wen;Shanshan Xie;Dan Yao;Xiaodong Liu;Guangji Wang ;Lin Xie
British Journal of Pharmacology 2010 Volume 159( Issue 7) pp:1511-1522
Publication Date(Web):
DOI:10.1111/j.1476-5381.2009.00634.x
Background and purpose: The multidrug resistance of epilepsy may result from the overexpression of P-glycoprotein, but the mechanisms are unclear. We investigated whether the overexpression of P-glycoprotein in the brains of subjects with pharmacoresistant epilepsy resulted from both drug effects and seizure activity.
Experimental approach: Kindled rats were developed by injecting a subconvulsive dose of pentylenetetrazole (33 mg·kg−1·day−1, i.p.) for 28 days. Groups were then treated with an oral dose of phenobarbital (45 mg·kg−1·day−1) for 40 days. In accord with behavioural observations, P-glycoprotein activity in brain was assessed using brain-to-plasma concentration ratios of rhodamine 123. P-glycoprotein levels in the brain regions were further evaluated using RT-PCR and Western blot analysis. The distribution of phenobarbital in the brain was assessed by measuring phenobarbital concentrations 1 h following its oral administration.
Key results: The kindling significantly increased P-glycoprotein activity and expression. Good associations were found among P-glycoprotein activity, expression and phenobarbital concentration in the hippocampus. Short-term treatment with phenobarbital showed good anti-epileptic effect; the maximum effect occurred on day 14 when overexpression of P-glycoprotein was reversed. Continuous treatment with phenobarbital had a gradually reduced anti-epileptic effect and on day 40, phenobarbital exhibited no anti-epileptic effect; this was accompanied by both a re-enhancement of P-glycoprotein expression and decreased phenobarbital concentration in the hippocampus. P-glycoprotein function and expression were also increased in age-matched normal rats treated with phenobarbital.
Conclusions and implications: The overexpression of P-glycoprotein in the brain of subjects with pharmacoresistant epilepsy is due to a combination of drug effects and epileptic seizures.
Co-reporter:Li Liu;Yun-Li Yu;Jian-Song Yang;Yang Li
Naunyn-Schmiedeberg's Archives of Pharmacology 2010 Volume 381( Issue 4) pp:371-381
Publication Date(Web):2010 April
DOI:10.1007/s00210-010-0502-0
Clinical reports have demonstrated that berberine is a potential antidiabetic agent, but the underlying mechanism is unclear. The purpose of this study was to investigate if berberine exerts its hypoglycemic action via inhibiting intestinal disaccharidases using in vivo and in vitro experiments. Streptozotocin-induced diabetic rats received berberine (100 or 200 mg/kg) orally once daily or acarbose (40 mg/kg) orally twice daily for 5 weeks. Disaccharidase activities and sucrase–isomaltase (SI) complex messenger RNA (mRNA) expression in intestinal regions were assessed. The same treatment was operated in normal rats. Sucrose and maltose loading tests were also documented. In addition, Caco-2 cells were cultured in medium containing berberine or berberine plus chelerythrine. Compound C or H-89 for 5 days, disaccharidase activities, and SI complex mRNA levels were measured. The animal experiments showed that berberine significantly decreased the disaccharidase activities and SI complex mRNA expression both in diabetic rats and normal rats. Berberine can also significantly lower postprandial blood glucose levels induced by sucrose or maltose loading in normal rats. The cellular results showed that berberine may suppress disaccharidase activities and downregulate SI complex mRNA expression in a concentration-dependent manner. Only H-89, an inhibitor of protein kinase A (PKA), may reverse the decrease in disaccharidase activities and SI complex mRNA expression induced by berberine. In conclusion, berberine suppresses disaccharidase activities and SI complex mRNA expression with beneficial metabolic effects in diabetic states. The inhibitory effect, at least partly, involves the PKA-dependent pathway.
Co-reporter:Dian-Lei Wang;Yan Liang;Lin Xie;Tong Xie;X. T. Wang;Sen Yu
Chromatographia 2008 Volume 67( Issue 3-4) pp:219-224
Publication Date(Web):2008 February
DOI:10.1365/s10337-007-0499-9
To evaluate the pharmacokinetics of a novel analogue of ginkgolide B, 10-O-dimethylaminoethylginkgolide B (XQ-1) in rat plasma in pre-clinical studies, a sensitive and specific liquid chromatographic method with electrospray ionization mass spectrometry detection (LC–ESI–MS) was developed and validated. After a simple extraction with ethyl acetate, XQ-1 was analyzed on a Shim-pack C18 column with a mobile phase of a mixture of 1 μmol L−1 ammonium acetate containing 0.02% formic acid and methanol (55:45, v/v) at a flowrate of 0.3 mL min−1. Detection was performed in selected ion monitoring (SIM) mode using target ions at [M + H]+m/z 496.05 for XQ-1 and m/z 432.10 for the internal standard (lafutidine). Linearity was established for the concentration range from 2 to 1,000 ng mL−1 . The extraction recoveries ranged from 86.0 to 89.9% in plasma at concentrations of 5, 50, and 500 ng mL−1. The lower limit of quantification was 2 ng mL−1 with 100 μL plasma. The validated method was successfully applied to a pharmacokinetic study after intragastic administration of XQ-1 mesylate in rats at a dose of 20 mg kg−1.
Co-reporter:Can Liu, Meng-yue Hu, Mian Zhang, Feng Li, Jia Li, Ji Zhang, Ying Li, Hai-fang Guo, Ping Xu, Li Liu, Xiao-dong Liu
Metabolism (October 2014) Volume 63(Issue 10) pp:1342-1351
Publication Date(Web):1 October 2014
DOI:10.1016/j.metabol.2014.06.015
ObjectiveGinsenosides, major bioactive constituents in Panax ginseng, have been shown to exert anti-hyperlipidemia effects. However, the underlying mechanism was not well-elucidated due to the low bioavailability of ginsenosides. Glucagon-like peptide-1 (GLP-1) was considered to be a critical regulator of energy homeostasis. Our previous studies have showed that ginseng total saponins (GTS) exhibited antidiabetic effects partly via modulating GLP-1 release. The aim of this study was to investigate the potential role of GLP-1 in anti-hyperlipidemia effect of GTS in rats fed with high-fat diet.Material and methodsMale Sprague–Dawley rats were fed with normal diet (CON) or high-fat diet (HFD) for 4 weeks. Then, the HFD rats orally received vehicle (HFD), 150 mg/kg/day (HFD-GL) and 300 mg/kg/day of GTS (HFD-GH) for another 4 weeks, respectively.ResultsFour-week GTS treatment significantly ameliorated hyperlipidemia, decreased body fat, liver weight and improved insulin resistance. It was found that high-dose GTS treatment increased portal GLP-1 level induced by glucose loading, accompanied by increased intestinal GLP-1 content, L-cell number and prohormone convertase 3 mRNA expression. Data from NCI-H716 cells showed that both GTS and ginsenoside Rb1 significantly increased GLP-1 secretion as well as proglucagon mRNA level in NCI-H716 cells supplemented with 10% HFD-rat serum.ConclusionsHyperlipidemia and insulin resistance were attenuated effectively in response to GTS treatment. These improvements may be associated with the increased secretion of GLP-1.
Co-reporter:Yun-ru Peng, You-bin Li, Xiao-dong Liu, Jian-feng Zhang, Jin-ao Duan
Phytomedicine (November 2008) Volume 15(Issue 11) pp:1016-1020
Publication Date(Web):1 November 2008
DOI:10.1016/j.phymed.2008.02.021
The antitumor activities of six C-21 steroidal glycosides isolated from the root tuber of Cynanchum auriculatum Royle ex Wight were performed according to a microculture tetrazolium (MTT) method on human tumor cell lines SMMC-7721, MCF-7 and Hela. Of these compounds, caudatin-2,6-dideoxy-3-O-methy-β-d-cymaropyranoside and caudatin were found to be of the highest effects against human tumor cell line SMMC–7721 with IC50 values of 13.49 and 24.95 μM, respectively. Then the in vivo assay further showed that caudatin-2,6-dideoxy-3-O-methy-β-d-cymaropyranoside and caudatin significantly inhibited the growth of transplantable H22 tumors in mice.
Co-reporter:Shuwen Jiang, Weiman Zhao, Yang Chen, Zeyu Zhong, ... Xiaodong Liu
Drug Metabolism and Pharmacokinetics (June 2015) Volume 30(Issue 3) pp:240-246
Publication Date(Web):1 June 2015
DOI:10.1016/j.dmpk.2015.02.004
Accumulating evidences have shown that diabetes is often accompanied with depression, thus it is possible that oral antidiabetic agent glyburide and antidepressive agent paroxetine are co-administered in diabetic patients. The aim of this study was to assess interactions between glyburide and paroxetine in rats. Effect of paroxetine on pharmacokinetics of orally administered glyburide was investigated. Effect of naringin (NAR), an inhibitor of rat intestinal organic anion transporting polypeptides 1a5 (Oatp1a5), on pharmacokinetics of glyburide was also studied. The results showed that co-administration of paroxetine markedly reduced plasma exposure and prolonged Tmax of glyburide, accompanied by significant increase in fecal excretion of glyburide. Co-administration of naringin also significantly decreased plasma exposure of glyburide. Data from intestinal perfusion experiments showed that both paroxetine and naringin significantly inhibited intestinal absorption of glyburide. Caco-2 cells were used to investigate whether paroxetine and naringin affected intestinal transport of glyburide and fexofenadine (a substrate of Oatp1a5). The results showed that both paroxetine and naringin greatly inhibited absorption of glyburide and fexofenadine. All results gave a conclusion that co-administration of paroxetine decreased plasma exposure of glyburide in rats via inhibiting intestinal absorption of glyburide, which may partly be attributed to the inhibition of intestinal Oatp1a5 activity.
Co-reporter:Qiushi Xie, Yang Chen, Fei Liu, Zeyu Zhong, ... Xiaodong Liu
Drug Metabolism and Pharmacokinetics (August 2016) Volume 31(Issue 4) pp:314-322
Publication Date(Web):1 August 2016
DOI:10.1016/j.dmpk.2016.05.002
Deoxypodophyllotoxin (DPT) is a natural lignan product which has drawn much attention due to its pharmacological properties including antitumor effect. The purpose of this study was to investigate interspecies differences in metabolism of DPT in hepatic microsomes from human (HLM), cynomolgus monkey (CyLM), rat (RLM), mouse (MLM) and dog (DLM). Incubation of DPT with hepatic microsomes from five species in the presence of NADPH resulted in formation of seven metabolites, five of which were compared with the synthetic standards. M2 was the most abundant metabolite in microsomes from all species. Rank order of intrinsic clearance for M2 formation was RLM > CyLM > MLM > HLM > DLM. In HLM, sulfaphenazole showed the strongest inhibition effect on M2 formation, but neither ticlopidine nor ketoconazole inhibited M2 formation in HLM. Results from cDNA-expressed human CYP450s experiments showed that clearance of M2 formation was much higher in CYP2C9 and CYP2C19 than that in CYP3A4. Contributions of the three CYP450 isoforms to M2 formation in HLM were estimated using relative activity factor (RAF) method or correction by amount of CYP450 isoforms in HLM. M2 formation in HLM was mainly attributed to CYP2C9, followed by CYP2C19. Involvement of CYP3A4 was minor.Download high-res image (156KB)Download full-size image
Co-reporter:Haifang Guo, Can Liu, Jia Li, Mian Zhang, ... Xiaodong Liu
Journal of Pharmaceutical Sciences (August 2013) Volume 102(Issue 8) pp:2819-2836
Publication Date(Web):1 August 2013
DOI:10.1002/jps.23613
Cytochrome P450 (CYP) 3A induction-mediated drug–drug interaction (DDI) is one of the major concerns in drug development and clinical practice. The aim of the present study was to develop a novel mechanistic physiologically based pharmacokinetic (PBPK)-enzyme turnover model involving both intestinal and hepatic CYP3A induction to quantitatively predict magnitude of CYP3A induction-mediated DDIs from in vitro data. The contribution of intestinal P-glycoprotein (P-gp) was also incorporated into the PBPK model. First, the pharmacokinetic profiles of three inducers and 14 CYP3A substrates were predicted successfully using the developed model, with the predicted area under the plasma concentration–time curve (AUC) [area under the plasma concentration–time curve] and the peak concentration (Cmax) [the peak concentration] in accordance with reported values. The model was further applied to predict DDIs between the three inducers and 14 CYP3A substrates. Results showed that predicted AUC and Cmax ratios in the presence and absence of inducer were within twofold of observed values for 17 (74%) of the 23 DDI studies, and for 14 (82%) of the 17 DDI studies, respectively. All the results gave us a conclusion that the developed mechanistic PBPK-enzyme turnover model showed great advantages on quantitative prediction of CYP3A induction-mediated DDIs. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2819–2836, 2013
Co-reporter:Mian Zhang, Can Liu, Meng-yue Hu, Ji Zhang, ... Xiao-dong Liu
Journal of Pharmacological Sciences (April 2015) Volume 127(Issue 4) pp:430-438
Publication Date(Web):1 April 2015
DOI:10.1016/j.jphs.2015.03.001
Evidence has shown that hyperlipidemia is associated with retinoid dyshomeostasis. In liver, retinol is mainly oxidized to retinal by retinol dehydrogenases (RDHs) and alcohol dehydrogenases (ADHs), further converted to retinoic acid by retinal dehydrogenases (RALDHs). The aim of this study was to investigate whether high-fat diet (HFD) induced hyperlipidemia affected activity and expression of hepatic ADHs/RDHs and RALDHs in rats. Results showed that retinol levels in liver, kidney and adipose tissue of HFD rats were significantly increased, while plasma retinol and hepatic retinal levels were markedly decreased. HFD rats exhibited significantly downregulated hepatic ADHs/RDHs activity and Adh1, Rdh10 and Dhrs9 expression. Oppositely, hepatic RALDHs activity and Raldh1 expression were upregulated in HFD rats. In HepG2 cells, treatment of HFD rat serum inhibited ADHs/RDHs activity and induced RALDHs activity. Among the tested abnormally altered components in HFD rat serum, cholesterol reduced ADHs/RDHs activity and RDH10 expression, while induced RALDHs activity and RALDH1 expression in HepG2 cells. Contrary to the effect of cholesterol, cholesterol-lowering agent pravastatin upregulated ADHs/RDHs activity and RDH10 expression, while suppressed RALDHs activity and RALDH1 expression. In conclusion, hyperlipidemia oppositely altered activity and expression of hepatic ADHs/RDHs and RALDHs, which is partially due to the elevated cholesterol levels.
Co-reporter:D. Yao, L. Liu, S. Jin, J. Li, X.-D. Liu
Neuroscience (27 December 2012) Volume 227() pp:283-292
Publication Date(Web):27 December 2012
DOI:10.1016/j.neuroscience.2012.10.006
Clinical studies and animal models have shown that pharmacoresistant epilepsy is partly due to the overexpression of ATP-binding cassette transporters at the brain. The purposes of the study were to investigate the function and expression of multidrug resistance-associated protein 2 (Mrp2) in the brain of pentylenetetrazole (PTZ)-kindled rats, and the effect of the altered Mrp2 function and expression on phenytoin (PHT) distribution in the brain. Kindled rats were developed by sub-convulsive dose of PTZ (33 mg/kg, every day, intraperitoneal (i.p.)) for 28 days. Mrp2 expression and function were measured by western blot and bromosulfophthalein (BSP) distribution in the brain. PHT concentrations in the brain of PTZ-kindled rats were measured alone or with co-administration of probenecid (50 mg/kg). Further experiment was designed to investigate whether PHT treatment prevented the up-regulated brain Mrp2 expression and function induced by PTZ-kindling. The results showed that PTZ-kindling resulted in an increase of Mrp2 level in the hippocampus and cortex of rats, accompanied by significant decreases in the brain-to-plasma concentration ratio of BSP. PTZ-kindling also decreased PHT levels in the hippocampus and cortex without altering PHT concentrations in plasma, resulting in a lower brain-to-plasma concentration ratio of PHT. Co-administration of probenecid increased the brain-to-plasma ratio of BSP and PHT in the brain of both normal and PTZ-kindled rats. A 14-day PHT treatment prevented the up-regulation of Mrp2 expression and function induced by PTZ-kindling, accompanied by increases of PHT concentrations in the brain and good anticonvulsive effects. The present study demonstrated that chronic PTZ-kindling increased Mrp2 expression and function in the rat brain, and the up-regulation partly came from epileptic seizure.Highlights► PTZ-kindled rats showed up-regulation of Mrp2 expression and function in the brain. ► Mrp2 function change affected PHT distribution in the brain of PTZ-kindled rats. ► PHT treatment prevented the up-regulation of Mrp2 expression and function induced by PTZ-kindling.
Co-reporter:Xian Pan, Ping Wang, Nan Hu, Li Liu, ... Guangji Wang
Drug Metabolism and Pharmacokinetics (2011) Volume 26(Issue 4) pp:387-398
Publication Date(Web):1 January 2011
DOI:10.2133/dmpk.DMPK-10-RG-126
Clinical studies have revealed that some fluoroquinolones may cause severe adverse effects when co-administered with substrates of CYP1A2. Our previous study showed antofloxacin (ATFX) was responsible for mechanism-based inhibition (MBI) of the metabolism of phenacetin in rats. In the clinical setting, ATFX is likely to be administrated with theophylline (TP), which is mainly metabolized by CYP1A2. The aim of the present study was to investigate the possible mechanism of TP/ATFX interaction. In vitro studies showed that the inhibitory effect of ATFX on the formation of three TP metabolites depended on NADPH, the pre-inhibition time, and ATFX concentration, i.e., factors which characterize MBI. In vivo studies demonstrated that single-dose ATFX (20 mg/kg) did not affect the pharmacokinetic behavior of TP, but multidose ATFX (20 mg/kg b.i.d. for 7.5 days) significantly increased the AUC of TP, decreased the amount of three TP metabolites in urine, and suppressed hepatic microsomal activity. A physiologically based pharmacokinetic (PBPK) model characterizing MBI of the three TP metabolites was developed for predicting TP/ATFX interaction in rats; this model was further extrapolated to humans. The predicted results were in good agreement with observed data. All the results indicated that ATFX was responsible for MBI of the metabolism of TP, and the PBPK model characterizing MBI may give good prediction of TP/ATFX interaction.
Co-reporter:Jian Wang, Sumei Xia, Weifang Xue, Dawei Wang, Yang Sai, Li Liu, Xiaodong Liu
European Journal of Pharmaceutical Sciences (20 November 2013) Volume 50(Issues 3–4) pp:290-302
Publication Date(Web):20 November 2013
DOI:10.1016/j.ejps.2013.07.012
Verapamil and its major metabolite norverapamil were identified to be both mechanism-based inhibitors and substrates of CYP3A and reported to have non-linear pharmacokinetics in clinic. Metabolic clearances of verapamil and norverapmil as well as their effects on CYP3A activity were firstly measured in pooled human liver microsomes. The results showed that S-isomers were more preferential to be metabolized than R-isomers for both verapamil and norverapamil, and their inhibitory effects on CYP3A activity were also stereoselective with S-isomers more potent than R-isomers. A semi-physiologically based pharmacokinetic model (semi-PBPK) characterizing mechanism-based auto-inhibition was developed to predict the stereoselective pharmacokinetic profiles of verapamil and norverapamil following single or multiple oral doses. Good simulation was obtained, which indicated that the developed semi-PBPK model can simultaneously predict pharmacokinetic profiles of S-verapamil, R-verapamil, S-norverapamil and R-norverapamil. Contributions of auto-inhibition to verapamil and norverapamil accumulation were also investigated following the 38th oral dose of verapamil sustained-release tablet (240 mg once daily). The predicted accumulation ratio was about 1.3–1.5 fold, which was close to the observed data of 1.4–2.1-fold. Finally, the developed semi-PBPK model was further applied to predict drug–drug interactions (DDI) between verapamil and other three CYP3A substrates including midazolam, simvastatin, and cyclosporine A. Successful prediction was also obtained, which indicated that the developed semi-PBPK model incorporating auto-inhibition also showed great advantage on DDI prediction with CYP3A substrates.Download high-res image (134KB)Download full-size image
Co-reporter:Y. Liu, H. Liu, J. Yang, X. Liu, ... G. Wang
Neuroscience (15 May 2008) Volume 153(Issue 3) pp:796-802
Publication Date(Web):15 May 2008
DOI:10.1016/j.neuroscience.2008.03.019
The aims of the study were to investigate whether the level of amyloid β-peptide (Aβ) (1–40) was increased in brain of diabetic rats and whether the increase was associated with dysfunction of P-glycoprotein at the blood–brain barrier. A diabetes-like condition was induced by single administration of 65 mg/kg streptozotocin via i.p. injection. Aβ (1–40) levels in brain of the diabetic rats were measured using an enzyme linked immunosorbent assay (ELISA) kit. The in vivo brain-to-blood efflux and blood-to-brain influx transport of [125I]-labeled human amyloid-β-peptide (hAβ) (1–40) were measured using the brain efflux index and brain permeability coefficient-surface area product, respectively. [14C]inulin served as a reference compound. The results showed that Aβ (1–40) levels significantly increased in temporal cortex and hippocampus of the diabetic rats. The brain remaining percentage of [125I]hAβ (1–40) in diabetic rats significantly increased at 30 min after intracerebral microinjection, accompanied by decrease of the brain efflux index. Pretreatment of P-glycoprotein inhibitors verapamil or cyclosporin A significantly increased the brain remaining percentage of [125I]hAβ (1–40). The brain permeability coefficient-surface area product of [125I]hAβ (1–40) was increased in diabetic rats, accompanied by increased Aβ (1–40) levels in plasma. The present study demonstrated that a diabetic state could increase Aβ (1–40) levels in brain, which might be explained, at least in part, by the decline in brain-to-blood efflux of Aβ (1–40) due to deficient cerebral P-glycoprotein function in diabetic rats.
Co-reporter:Zhaoli Ling, Nan Shu, Ping Xu, Fan Wang, Zeyu Zhong, Binbin Sun, Feng Li, Mian Zhang, Kaijing Zhao, Xiange Tang, Zhongjian Wang, Liang Zhu, Li Liu, Xiaodong Liu
Biochemical Pharmacology (15 January 2016) Volume 100() pp:98-111
Publication Date(Web):15 January 2016
DOI:10.1016/j.bcp.2015.11.023
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