PHARMAZIE
·
2012
·Vol. 67
·期 5
·426-431
·
IF 1.006
Sun Xiaoyi,Chen Jinliang,Chen Hailiang,Liang Wenquan
The transfection agent polycation polyethylenimine (PEI) has been rarely used to construct liposomes for chemical antitumor drugs. In this study, it was introduced into cisplatin (CDDP) encapsulated neutral liposomes (CDDP-NL) by amphiphilic PEI-cholesterol (PEI-Chol) to investigate
its effect on the antitumor activity in A549 cells. The IC50 was 0.65 ± 0.02, 2.94 ± 0.21 and 2.03 ± 0.15 g/ml for CDDP-cationic liposomes (CDDP-CL), CDDP-NL and free CDDP, respectively. The enhanced anticancer activity was attributed to the addition of PEI-Chol
which influenced cellular processing of CDDP. With the help of inhibitors, we found that besides clathrin dependent and actin dependent uptake pathways, caveolae-mediated endocytosis was involved in the internalization of CDDP-CL. Improved internalization of CDDP was observed. Intracellular
Pt accumulations were 6.5 times and 3 times of those in CDDP-NL and free CDDP groups, respectively. The differences of intracellular location caused by endocytosis routes and lysosomes escape capacity of PEI-Chol was observed by fluorescence colocalization studies. PEI-Chol also decreased
the Pt fraction exported out of cells and extended the cellular Pt retention of CDDP liposomes. In conclusion, cationic modification of liposomes with PEI is a potential and promising way for antitumor drug delivery.
研究领域:
药理学
·
肿瘤学
·
药物递送系统
·
细胞生物学
✓ 已验证
产品关联
DOI
高影响因子
PHARMAZIE
·
2012
·Vol. 67
·期 8
·715-717
·
IF 1.006
Fu Jian-Fang,Ren Qin-You,Zhang Nan-Yan,Gao Bin,Tu Yan-Yang,Fu Guo-Qiang,Li Dao-Hai,Zhang Yong-Sheng
The aim of the present study was to investigate the inhibitory potential of glimepiride towards important UDP-glucuronosyltransferase (UGT) isoforms in human liver, which play a key role in the elimination of drugs. The recombinant UGT enzymes were used as enzyme source, and a nonspecific
substrate 4-methylumbelliferone (4-MU) was utilized as substrate. The results showed that 100 μM of glimepiride inhibited UGT1A1, UGT1A3, UGT1A6, UGT1A9, UGT2B7 and UGT2B15 by 54.7%, 43.1%, 100%, 70.5%, 32.7 and 37.2%, respectively. Given that glimepiride exhibited strong inhibition towards
UGT1A6, further inhibitory kinetic behaviour was determined. Glimepiride exerted concentration-dependent inhibition towards UGT1A6. Both Dixon and Lineweaver-Burk plots demonstrated that inhibition of UGT1A6 was best fit for noncompetitive inhibition type, and the inhibition kinetic parameter
(Ki) was calculated to be 59.8 μM. Given that UGT1A6 plays a key role in detoxification of many drugs, more attention should be given when glimepiride was co-administered with the drugs mainly undergoing UGT1A6-mediated metabolism.
研究领域:
药理学
·
临床医学
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产品关联
DOI
高影响因子
PHARMAZIE
·
2012
·Vol. 67
·期 9
·804-808
·
IF 1.006
Liu Xiao-You,Fang Zhong-Ze,Dong Pei-Pei,Shi Xiang-Hua,Sun Xu-Yong,Teng Yan-Jie
The objective of the present study is to clearly evaluate the inhibitory effects of tacrolimus (tacro) on important UGT isoforms in human liver, including determination of inhibition kinetic type and calculation of inhibition kinetic parameters. An in vitro incubation system
was used to investigate the inhibitory effect of tacro on UGT isoforms. The recombinant UGT isoforms were used as enzyme source, and a nonspecific substrate 4-methylumbelliferone (4-MU) was utilized as substrate. Among the tested UGT isoforms, UGT1A1, UGT1A3, UGT2B7 and UGT2B15 were strongly
inhibited by tacro in a concentration-dependent manner. Dixon and Lineweaver-Burk plots showed that the inhibition of UGT1A1, UGT1A3, and UGT2B7 was all best fit to competitive inhibition type, and the inhibition of UGT2B15 was best fit to noncompetitive type. The inhibition kinetic parameters
(Ki) were determined to be 4.7, 1.3, 1.9, and 4.3 M for UGT1A1, UGT1A3, UGT2B7, and UGT2B15, respectively. Inhibition of these important UGT isoforms in human liver might be an important reason for clinically frequent drug-drug interaction between tacro and other drugs.
研究领域:
药理学
·
生物化学
·
临床医学
✓ 已验证
DOI
高影响因子
PHARMAZIE
·
2012
·Vol. 67
·期 12
·1002-1006
·
IF 1.006
Dong Rui-Hua,Fang Zhong-Ze,Zhu Liang-Liang,Ge Guang-Bo,Cao Yun-Feng,Li Xiao-Bao,Hu Cui-Min,Yang Ling,Liu Ze-Yuan
Carvacrol and thymol are phenolic compounds with similar structures isolated from many aromatic plants, and have been demonstrated to exert multiple pharmacological effects. The metabolic and pharmacokinetic behaviour of thymol and carvacrol has received much attention. Carvacrol and
thymol have been demonstrated to undergo phase I metabolism such as hydroxylation reaction. However, drug-metabolizing enzymes involved in this process remain unclear. Given that cytochrome P450 s (CYPs) are involved in most phase I metabolism, the aim of the present study was to investigate
the role of CYPs in the metabolism of thymol and carvacrol. After incubation with human liver microsomes (HLMs) in the presence of NADPH, a new metabolite and two metabolites were detected for thymol and carvacrol, respectively. A combination of chemical inhibition studies and assays with
recombinant CYP isoforms demonstrated that CYP2A6 was the predominant drug-metabolizing enzyme involved in the metabolism of thymol and carvacrol. All these results remind the researchers that special attention should be paid on pharmacokinetic and clinical outcomes when thymol or carvacrol
was co-administrated with other compounds mainly undergoing CYP2A6-mediated metabolism.
研究领域:
药理学
·
生物化学
✓ 已验证
产品关联
DOI
高影响因子
PHARMAZIE
·
2020
·Vol. 75
·期 5
·186-190
·
IF 1.198
Qin Yanjie,Wang Nanxi,Chen Fen,Han Xuemei,Zhu Ying,Rang Ying,Zhai Xuejia,Lu Yongning
Irinotecan (CPT-11) is a broad spectrum agent for the treatment of solid tumor malignancies, despite severe diarrhea is limiting its widespread usage. The local effects of SN-38 in the small intestine were considered to be responsible for the irinotecan-induced delayed diarrhea. It
was proposed that cyclosporin A (CsA) inhibiting biliary excretion could attenuate this side effect, but in fact, it could not improve the therapeutic index of irinotecan. At present, most studies focused on the inhibition of bile excretion by cyclosporin A through the transporters MRP2 and
MDR1 and its effect the irinotecan treatment in vivo. However, UDP glucuronyltransferase-1 polypeptide A1 (UGT1A1) was related to a significantly altered disposition of irinotecan and its metabolites, and was therefore associated with irinotecan-induced toxicity. This study focused
on UGT1A1-mediated conversion of SN-38 to SN-38G, and systematically investigated the CsA-irinotecan interactions in vitro and in vivo. After treatment with 10 mg·kg-1 CsA for 7 days, the bile excretion of irinotecan and its metabolites decreased and AUC0-∞
increased significantly. The AUC0-∞ (SN-38G)/AUC0-∞ (SN-38) was significantly reduced when compared with that in vehicle-treated rats. In the liver microsome incubation system, the IC50 of CsA for UGT1A1 enzyme was 9.4 μM. Furthermore, the UGT1A1
mRNA and protein expression levels were significantly reduced. The present study indicated that CsA treatment could enhance the systemic exposure and toxicity of SN-38 by inhibiting the UGT1A1 enzyme. The inhibition of UGT1A1 enzyme might be a critical factor in the failure of CsA improving
irinotecan's treatment index.
研究领域:
药理学
·
肿瘤学
·
毒理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHARMAZIE
·
2021
·Vol. 76
·期 5
·195-201
·
IF 1.267
Dai Tianming,Wang Min,Wang Pengzhen,Dai Libing,Dai Renke,Meng Qingqi
The effects of eight oral anti-coronavirus drugs (lopinavir, ritonavir, chloroquine, darunavir, ribavirin, arbidol, favipiravir, oseltamivir) on the metabolism of four specific glycosides (polydatin, geniposide, quercitrin, glycyrrhizin) and on the activities of three major glycosidases
(β-glucosidase, α-rhamnosidase, β-glucuronidase) from gut microflora were explored in vitro and determined by LC-MS/MS. The metabolism of polydatin, geniposide, quercitrin and glycyrrhizin was significantly inhibited by one or several anti-coronavirus drugs of 100 μM
around 1 h and 4 h (P<0.05), among which darunavir could strongly reduce the production of genipin (70.6% reduction), quercitin (80.6% reduction) and glycyrrhetinic acid (37.9% reduction), which may cause a high risk of herb-drug interactions (HDI). Additionally, chloroquine reduced the
production of genipin and quercitin by more than 75% (P<0.05), whereas arbidol had no significant influence on the metabolism of polydatin, quercitrin and glycyrrhizin (P>0.05) so that its risk may be lower. The inhibition of darunavir on β-glucosidase was relatively strong (IC50
= 193±23 μM), and the inhibition became weaker on β-glucuronidase and α-rhamnosidase (IC50>500 μM). The consistency between gut microflora and glycosidase system indicated that the inhibition of darunavir on the activity of β-glucosidase and β-glucuronidase
may be the main reason for affecting the metabolism of geniposide, glycyrrhizin and polydatin in gut microflora. However, for the inhibition of darunavir and chloroquine on the metabolism of quercetrin, there was no correlation between gut microflora and α-rhamnosidase system. Assessing
the risk of HDI mediated by glycosidases in gut microflora may be conducive to the safety and efficacy of combining traditional herbal and Western medicine for the treatment of patients with Covid-19.
研究领域:
药理学
·
微生物学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHARMAZIE
·
2020
·Vol. 75
·期 9
·424-429
·
IF 1.198
Chen Jiangfei,Guo Suhang,Yu Xianzhu,Lei Jinxiu,Xu Tao,Zhu Suyan,Chen Lu,Xu Ping,Zhou Xuan,Yu Lushan
Flumatinib, indicated for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia, is a structural analog of imatinib and has shown higher potency than imatinib as a BCR-ABL inhibitor. In this paper, the metabolic profile of flumatinib was studied. It was found that
CYP3A4 and CYP2C8 were the main cytochrome P450 enzyme substyles catalyzing the metabolism of flumatinib, and CYP3A4 has a stronger metabolic ability for flumatinib than CYP2C8. Erythromycin, cyclosporine, and voriconazole can inhibit the metabolism of flumatinib in vitro. Accordingly,
co-administration of erythromycin and cyclosporine with flumatinib increased the plasma concentration and the systemic exposure of flumatinib in rats, which indicated that lower doses should be considered in clinical practice.
研究领域:
药理学
·
肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHARMAZIE
·
2020
·Vol. 75
·期 10
·483-487
·
IF 1.198
Wang Lili,Liu Shuyu,Gao Ziyao
Berberine hydrochloride (BCl) is commercially used to treat diarrhea, diabetes, hyperlipidemia, and cancer. However, BCl suffers from solid state instability, low aqueous solubility, low dissolution rate, and poor bioavailability, which limit its potential application in clinical medicine.
In this work, we report a novel cocrystal hydrate of BCl with L(+)-lactic acid (BCl-LA-H2O), designed to improve its physicochemical properties, thus promoting its application in the pharmaceutical industry. As a result, the cocrystal strategy improved the solubility, dissolution,
melting point, and hygroscopicity of BCl, which indicated that the BCl-LA-H2O can be used as a better solid form.
研究领域:
药学
·
材料科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHARMAZIE
·
2018
·Vol. 73
·期 9
·503-507
·
IF 1.016
Liu Yixian,Wang Yafeng,Peng Youmei,Liu Bingjie,Ma Fang,Jiang Jinhua,Wang Qingduan,Chang Junbiao
The purpose of the present study was to dig into recent studies designed to characterize the impacts of 2'-deoxy-2'-β-fluoro-4'-azidocytidine (FNC) on P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2) and breast cancer resistance protein (BCRP). Specifically,
the modulation effects of FNC on P-gp, MRP2 and BCRP protein expressions were assessed by western blot methods. 5 (and 6)-Carboxy-2',7'-dichloroflourescein (CDF) and BODIPY-prazosin were used to provide indications of alterations of MRP2 and BCRP activities. The effects of P-gp, MRP2 and BCRP
on FNC were evaluated in the in situ single-pass intestinal perfusion model. The results showed that FNC at higher concentrations and with longer incubation times can upregulate the protein expression of P-gp, MRP2 and BCRP in Caco-2 cells. The upregulated proteins were also functionally
active, as revealed by a lower degree of CDF and BODIPY-prazosin uptake by the cell monolayers. The intestinal absorptive coefficient (Peff) was observed to significantly increase with the inhibitors of P-gp, MRP2 and BCRP. These results suggested that FNC could modulate the expressions and
functions of P-gp, MRP2 and BCRP, while P-gp, MRP2 and BCRP were involved in the efflux transport of FNC. The inductive effects of FNC on P-gp, MRP2 and BCRP suggested the possibility of FNC to contribute to the inter- and intra-individual variability of itself, as well as to alter the absorption
of other drugs that may be administered concomitantly.
研究领域:
药理学
·
分子生物学
·
药物代谢动力学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHARMAZIE
·
2016
·Vol. 71
·期 5
·269-273
·
IF 1.264
Zhu Chaoran,Zhai Xuejia,Chen Fen,Wang Nanxi,Zhang Xinlin,Lu Yongning
Capsaicin (CAP, trans-8-methyl-N-vanillyl-6-nonenamide) is a major pungent substance in hot pepper. However, little is known about the interactions between CAP and clinically used drugs. This study investigated the effect of acute and chronic ingestion of CAP on pharmacokinetics of
simvastatin (SV) and the mechanism of this CAP–drug intercation. CAP was orally administered at doses of 3 and 8 mg·kg-1 for seven consecutive days once daily and on the 1st day and the 7th day, SV (8 mg·kg-1) was injected intravenously. Plasma concentrations
of SV were determined using LC/MS/MS and expression of Ugt1a1 was analyzed by RT-qPCR and Western Blotting. We found that there were 78.0 % (P< 0.05) and 81.2% (P< 0.05) reduction in the AUC(0-∞) of SV, respectively, following pretreatment with two doses
of CAP. The AUC(0-∞) of SV in the two dose group pretreated with CAP for 7 days were decreased significantly, compared to the group for 1 day. Both the RT-qPCR and Western Blotting data indicated that 7 days pretreatment with CAP increased the expression level of Ugt1a1 in
liver. In conclusion, chronic ingestion of CAP enhanced the expression level of Ugt1a1 in liver, causing the food -drug interaction and decrease in SV exposure in rats to a significant extent.
研究领域:
药理学
·
分子生物学
·
毒理学
✓ 已验证
产品关联
DOI
高影响因子
PHARMAZIE
·
2014
·Vol. 69
·期 5
·362-366
·
IF 1.003
Kong L.M.,Xu S.Y.,Hu H.H.,Zhou H.,Jiang H.D.,Yu L.S.,Zeng S.
The aim of the present study was to develop the recombinant insect cell-expressed protein as an in vitro model for inhibitors screening for human cytochrome P450 2C19 (CYP2C19), and to use the model to investigate the inhibition effect of three phytochemicals on CYP2C19 in
vitro. Omeprazole was applied as the probe substrate. The estimated inhibitory constant (Ki) of ticlopidine and fluvoxamine were 0.64 ± 0.025 M and 0.29 ± 0.090 M, respectively. After co-incubation with ticlopidine or fluvoxamine, the mean omeprazole Michaelis-Menten
constant (Km) increased from 4.99 ± 0.22 M to 16.25 ± 1.22 M or 19.20 ± 1.73 M, respectively, while omeprazole's mean Vmax did not vary much. Both ticlopidine and fluvoxamine were competitive inhibitors of CYP2C19. The IC50 of three phytochemicals,
isoalantolactone, curcumol and schisandrin A was determined as 38.91 M, 121.0 M and 86.41 M, and the Ki as 5.02 ± 1.04 M, 35.84 ± 8.95 M, and 4.46 ± 0.017 M, respectively. The in vitro model for inhibitor screening established using recombinant CYP2C19
could be used to assess the inhibition potential of drug candidates. Isoalantolactone and schisandrin A are potent inhibitors of CYP2C19, while curcumol is a moderate potent inhibitor of CYP2C19.
研究领域:
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
高影响因子
PHARMAZIE
·
2014
·Vol. 69
·期 12
·898-903
·
IF 1.003
Xia Meng-Ming,Wang Li,Pan Pei-Pei,Wang Hai-Yun,Chen Meng-Chun,Chen Yi,Dai Da-Peng,Cai Jian-Ping,Hu Guo-Xin
CYP2C9 is one of four known members of the human cytochrome P450 CYP2C superfamily, with at least 57 CYP2C9 alleles being previously identified. Genetic polymorphisms of CYP2C9 significantly influence the efficacy and safety of some drugs, which might cause adverse effects and therapeutic
failure. The purpose of the present study was to clarify the role of 36 CYP2C9 alleles, 21 novel alleles (*36-*56) found in the Chinese population, in the oxidative metabolism of diclofenac in vitro. Insect microsomes expressing the 36 human CYP2C9 alleles were incubated with 2-100
μM diclofenac for 30 min at 37°C and terminated by the addition of 30 μL 0.1 M HCl. Diclofenac and 4'-hydroxyl (OH)-diclofenac, the major diclofenac metabolite, were analyzed by high-performance liquid chromatography (HPLC). Compared with wild-type CYP2C9*1, most variants
showed significantly altered values in Vmax, Km and intrinsic clearance (Vmax/Km). Only one variant exhibited markedly increased intrinsic clearance value, whereas 31 variants exhibited significantly decreased values. Thus, this study demonstrated
that more attention should be given to subjects carrying these CYP2C9 alleles when administering diclofena.
研究领域:
药理学
·
遗传学
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）