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1.
Biomed Pharmacother ; 125: 110032, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32187961

RESUMO

This study was devised to investigate if P-glycoprotein (P-gp) mediated the drug-drug interaction (DDI) between genistein and repaglinide. When genistein was added, the plasma concentrations of repaglinide in rats were increased. The maximum plasma concentration (Cmax) of repaglinide increased from 70.80 ± 7.98 ng/mL to 124.71 ± 9.02 ng/mL and the area under the plasma concentration-time curve (AUC) increased from 134.89 ± 13.65 µg·h/L to 245.95 ± 7.24 µg·h/L. Intestinal absorption of repaglinide was markedly enhanced by genistein or P-gp inhibitor verapamil (Ver), both in situ rat jejunal perfusion studies and in vitro transport assays using everted rat intestinal sac preparations. Furthermore, the accumulation of repaglinide in both Caco-2 cells and IEC-6 cells also increased significantly in the presence of genistein and Ver. The transepithelial transport rate of repaglinide from basolateral-to-apical in MDR1-MDCK cells was 3.6-fold higher than the apical-to-basolateral rate with a net efflux ratio of 1.92 compared with mock-MDCK cells, which was significantly decreased following co-administration with genistein or Ver. In an intracellular accumulation experiment using Rhodamine 123 as a P-gp substrate, genistein significantly increased the intracellular fluorescence of Rhodamine 123. These results indicated that genistein had an inhibitory effect on the efflux function of P-gp. Through molecular docking assays we further found that genistein could bind to the nucleotide-binding domains (NBD) in the cytoplasm of P-gp, thus affecting the functions of P-gp. In conclusion, genistein inhibited the efflux of repaglinide mediated by P-gp in rats and in vitro. The findings suggested that the DDI between genistein and repaglinide is mediated by P-gp, and a dosage adjustment may be needed when they are co-administered in a clinical setting.

2.
Drug Dev Res ; 2020 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-32220026

RESUMO

Scutellarin is the major and active constituent of Dengzhan Xixin Injection (DZXX), a traditional Chinese medicine prepared from the aqueous extract of Erigeron breviscapus and widely used for the treatment of various cerebrovascular diseases in clinic. In present study, the possible pharmacokinetic differences of scutellarin after intravenous administration of scutellarin alone or DZXX were explored. Additional, the potential roles of ß-glucuronidase (GLU) and OATP2B1 in drug-drug interaction (DDI) between scutellarin and constituents of DZXX were further evaluated in vitro. The plasma concentration, urinary and biliary excretion of scutellarin in rats after administration of DZXX, were significantly higher than those received scutellarin, while pharmacokinetic profile of Apigenin 7-O-glucuronide (AG) in rats was similar no matter AG or DZXX group. Furthermore, higher concentration in brain and plasma, however, lower level of scutellarin in intestine were observed after intravenous administration of DZXX. Finally, AG and caffeoylquinic acid esters were found to significantly inhibit GLU and OATP2B1 in vitro, which might explain, at least in part, the pharmacokinetic DDI between scutellarin and other chemical constituents in DZXX. The findings provided deep insight into the prescription-formulating principle in DZXX for treating the cerebrovascular diseases.

3.
Br J Pharmacol ; 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32000294

RESUMO

BACKGROUND AND PURPOSE: Diclofenac is a widely used nonsteroidal anti-inflammatory drug. However, adverse effects in the kidney limit its clinical application. The present study was aimed to evaluate the potential effect of cilastatin on diclofenac-induced acute kidney injury and to clarify the potential roles of renal organic anion transporters (OATs) in the drug-drug interaction between cilastatin and diclofenac. EXPERIMENTAL APPROACH: The effect of cilastatin was evaluated in diclofenac-induced acute kidney injury in mice. Human OAT1/3-transfected HEK293 cells and renal primary proximal tubule cells (RPTCs) were used to investigate OAT1/3-mediated transport and the cytotoxicity of diclofenac. KEY RESULTS: Cilastatin treatment decreased the pathological changes, renal dysfunction and elevated renal levels of oxidation products, cytokine production and apoptosis induced by diclofenac in mice. Moreover, cilastatin increased the plasma concentration and decreased the renal distribution of diclofenac and its glucuronide metabolite, diclofenac acyl glucuronide (DLF-AG). Similarly, cilastatin inhibited cytotoxicity and mitochondrial damage in RPTCs but did not change the intracellular accumulation of diclofenac. DLF-AG but not diclofenac exhibited OAT-dependent cytotoxicity and was identified as an OAT1/3 substrate. Cilastatin inhibited the intracellular accumulation and decreased the cytotoxicity of DLF-AG in RPTCs. CONCLUSION AND IMPLICATIONS: Cilastatin alleviated diclofenac-induced acute kidney injury in mice by restoring the redox balance, suppressing inflammation, and reducing apoptosis. Cilastatin inhibited OATs and decreased the renal distribution of diclofenac and DLF-AG, which further ameliorated the diclofenac-induced nephrotoxicity in mice. Cilastatin can be potentially used in the clinic as a therapeutic agent to alleviate the adverse renal reaction to diclofenac.

4.
J Cell Physiol ; 235(4): 3309-3319, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31587272

RESUMO

The aim of this study was to explore whether rhein could enhance the effects of pemetrexed (PTX) on the therapy of non-small-cell lung cancer (NSCLC) and to clarify the associated molecular mechanism. Our study shows that rhein in combination with PTX could obviously increase the systemic exposure of PTX in rats, which would be mediated by the inhibition of organic anion transporters (OATs). Furthermore, the toxicity of PTX was significantly raised by rhein in A549 cells in a concentration-dependent manner. Concomitant administration of rhein and PTX-induced cell apoptosis compared with PTX alone in flow cytometry assays, which was further validated by the protein expressions of the apoptotic markers B-cell lymphoma-2/Bcl-2-associated x (Bcl-2/Bax) and Cleaved-Caspase3 (Cl-Caspase3). Meanwhile, the results of monodansylcadaverine (MDC) dyeing experiments showed that PTX-induced autophagy could be enhanced by combination therapy with rhein in A549 cells. Western blot analysis indicated that the synergistic effect of rhein on PTX-mediated autophagy may be interrelated to PI3K-AKT-mTOR pathway inhibition and to the enhancement of p-AMPK and light chain 3-II (LC3-II) protein levels. From these findings, it could be surmised that rhein enhanced the antitumor activity of PTX through influencing autophagy and apoptosis by modulating the PI3K-AKT-mTOR pathway and Bcl-2 family of proteins in A549 cells. Our findings demonstrated that the potential application of rhein as a candidate drug in combination with PTX is promising for treatment of the human lung cancer.

5.
Int J Biol Macromol ; 143: 349-358, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31830453

RESUMO

ß-Glucuronidase plays a vital role in the metabolism of drugs and endogenous substance. Herein, we assayed the inhibitory effects of thirty-six flavonoids (1-36) toward ß-glucuronidase (Escherichia coli) using the probe reaction of DDAO-glu hydrolysis. The results showed that kushenol X (6), (2S)-farrerol (10), 5,7,2'-trihydroxy-8,6'-dimethoxy flavone (20), demethylbellidifolin (31), and gentisin (32) exhibited potent inhibitory activities toward ß-glucuronidase with the IC50 values of 2.07 ± 0.26, 8.95 ± 0.74, 4.97 ± 0.61, 0.91 ± 0.11, and 0.68 ± 0.10 µM, respectively. Furthermore, the inhibition kinetics studies indicated that demethylbellidifolin (31) and gentisin (32) exhibited mixed-type inhibiton toward ß-glucuronidase, the Ki values were caculated to be 4.05 and 2.02 µM, respectively. Additionally, the circular change of dichroism (CD) spectrum verified the interaction between demethylbellidifolin (31) and gentisin (32) with ß-glucuronidase; following by the molecular docking and molecular dynamics further revealed the potential interaction amino acid site in ß-glucuronidase. All our findings not only developed some potent novel ß-glucuronidase inhibitors but also indicated the potential herb drug interaction (HDI) effects of flavonoids with some clinical drugs which had enterohepatic circulation and further revealed the vital pharamcophoric requirement of natural flavonoids for ß-glucuronidase inhibition activity.

6.
J Nat Prod ; 82(12): 3302-3310, 2019 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-31789520

RESUMO

Nine new monoterpenoid indole alkaloids, uncarialins A-I (1-9), were isolated from Uncaria rhynchophylla as well as 14 known analogues (10-23). Their structures were determined by HRESIMS, 1D and 2D NMR, and experimental and calculated electronic circular dichroism data. Compounds 5, 7, 15, and 22 displayed significant agonistic effects against the 5-HT1A receptor with EC50 values of 2.2 ± 0.1, 0.1 ± 0.1, 1.6 ± 0.3, and 2.0 ± 0.5 µM, respectively. The mechanisms of action of these four compounds with the 5-HT1A receptor were investigated by molecular docking, and the results suggested that amino acid residues Asp116, Thr196, Asn386, and Tyr390 played critical roles in the observed activity of the above-mentioned compounds.

7.
Future Med Chem ; 11(22): 2891-2903, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31702381

RESUMO

Aim: CYP3A5 plays a vital role in the drug metabolism, it displays varied expression levels among individuals and is easily influenced by genetic polymorphisms and some diseases. Methodology & results: A dual function probe isobutyryl-11-keto-ß-boswellic acid (IKBA) was developed; it possessed a high selectivity toward CYP3A5 and CYP3A enzymes for its two individual metabolites, respectively. The probe has the high accuracy and wide applicability in measuring the real activity of CYP3A5. Finally, IKBA was successfully used for the evaluation of the activity of CYP3A5 and CYP3A enzymes in various bio samples. Conclusion: IKBA could serve as a useful tool for exploring the physiology and pathology functions of CYP3A5 and give some useful guidance for the rational use of clinical drugs.

8.
Acta Pharm Sin B ; 9(5): 986-996, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31649848

RESUMO

Imipenem is a carbapenem antibiotic. However, Imipenem could not be marketed owing to its instability and nephrotoxicity until cilastatin, an inhibitor of renal dehydropeptidase-I (DHP-I), was developed. In present study, the potential roles of renal organic anion transporters (OATs) in alleviating the nephrotoxicity of imipenem by cilastatin were investigated in vitro and in rabbits. Our results indicated that imipenem and cilastatin were substrates of hOAT1 and hOAT3. Cilastatin inhibited hOAT1/3-mediated transport of imipenem with IC50 values comparable to the clinical concentration, suggesting the potential to cause a clinical drug-drug interaction (DDI). Moreover, imipenem exhibited hOAT1/3-dependent cytotoxicity, which was alleviated by cilastatin and probenecid. Furthermore, cilastatin and probenecid ameliorated imipenem-induced rabbit acute kidney injury, and reduced the renal secretion of imipenem. Cilastatin and probenecid inhibited intracellular accumulation of imipenem and sequentially decreased the nephrocyte toxicity in rabbit primary proximal tubule cells. Renal OATs, besides DHP-I, was also the target of interaction between imipenem and cilastatin, and contributed to the nephrotoxicity of imipenem. This therefore gives in part the explanation about the mechanism by which cilastatin protected against imipenem-induced nephrotoxicity. Thus, OATs can potentially be used as a therapeutic target to avoid the renal adverse reaction of imipenem in clinic.

9.
Eur J Med Chem ; 182: 111652, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31494470

RESUMO

Farnesoid X receptor (FXR) is a key regulator in charge of bile acid synthesis, transport, and metabolism. Activation of FXR represses bile acid synthesis and increases its excretion and transport, consequently protecting the liver functions. Thus, FXR is considered as a critical therapeutic target of cholestasis and nonalcoholic steatohepatitis. Herein, we isolated and identified fourteen new protostane-type triterpenoids (1-14) and four known analogues (15-18) from Alisma orientale, and finally constructed a small library of protostane-type triterpenoids (1-70) to investigate their structure-activity relationship with FXR, further leading to obtain compound 15 with potent agonistic activity against FXR (EC50 = 90 nM). Extensive in vitro investigation confirmed high efficacy of compound 15 against FXR in living cell, and revealed its underlying mechanism for FXR activation (amino acid residues Arg331 and Ser332) by molecular docking and site-directed mutagenesis technology.


Assuntos
Produtos Biológicos/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Terpenos/farmacologia , Alisma/química , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Células Cultivadas , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Mutagênese Sítio-Dirigida , Receptores Citoplasmáticos e Nucleares/genética , Relação Estrutura-Atividade , Terpenos/química , Terpenos/isolamento & purificação
10.
Br J Pharmacol ; 176(23): 4558-4573, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31378931

RESUMO

BACKGROUND AND PURPOSE: Catalpol, a water-soluble active ingredient isolated from Rehmannia glutinosa, exhibits multiple pharmacological activities. However, the mechanism(s) underlying protection against renal injury by catalpol remains unknown. EXPERIMENTAL APPROACH: Adriamycin-induced kidney injury models associated with podocyte damage were employed to investigate the nephroprotective effects of catalpol. In vivo, TUNEL and haematoxylin-eosin staining was used to evaluate the effect of catalpol on kidney injury in mice. In vitro, effects of catalpol on podocyte damage induced by adriamycin was determined by elisa kit, flow cytometry, Hoechst 33342, and TUNEL staining. The mechanism was investigated by siRNA, EX527, and docking simulations. KEY RESULTS: In vivo, catalpol treatment significantly improved adriamycin-induced kidney pathological changes and decreased the number of apoptotic cells. In vitro, catalpol markedly decreased the intracellular accumulation of adriamycin and reduced the calcium ion level in podocytes and then attenuated apoptosis. Importantly, the regulatory effects of catalpol on sirtuin 1 (SIRT1), multidrug resistance-associated protein 2 (MRP2), and the TRPC6 channel were mostly abolished after incubation with SIRT1 siRNA or the SIRT1-specific inhibitor EX527. Furthermore, docking simulations showed that catalpol efficiently oriented itself in the active site of SIRT1, indicating a higher total binding affinity score than that of other SIRT1 activators, such as resveratrol, SRT2104, and quercetin. CONCLUSION AND IMPLICATIONS: Taken together, our results suggest that catalpol exhibits strong protective effects against adriamycin-induced nephropathy by inducing SIRT1-mediated inhibition of TRPC6 expression and enhancing MRP2 expression.

11.
J Mater Chem B ; 7(32): 4983-4989, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31411622

RESUMO

Glutathione transferase (GST) is a very important metabolic enzyme that mediates the wide metabolism of endogenous and xenobiotic compounds; it usually has a significant over expression in cancer cells, which is a key reason resulting in drug resistance, and will show an obvious down regulation during liver injury, thus it was also regarded as a vital biomarker in clinical diagnosis. Herein, based on boron-dipyrromethene (BODIPY) dye, a two-photon probe BNPA was designed for the real-time detection of GST activities and fluorescence imaging in both cancer cells and liver tissues. Importantly, BNPA exhibited a high selectivity, ultrahigh imaging resolution and showed a classic Michaelis-Menten kinetics toward GSTs. Furthermore, it was successfully used for monitoring the GST activities in living cells and deep tissues by two-photon imaging, as well as detecting the down regulation of GST activities during α-naphthylisothiocyanate (ANIT) induced liver injury. Our results fully demonstrated that BNPA could serve as a promising tool for evaluating the GST function and the process of cellular GSTs in living systems, and also provided a new approach for studying GST-associated liver diseases, which would be greatly useful for rational drug use and disease diagnosis in clinics.

15.
Bioorg Chem ; 90: 103101, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31291611

RESUMO

In this study, forty-nine kinds of traditional Chinese medicines (TCMs) were evaluated for their inhibitory activities against human carboxylesterase 2 (HCE 2) using a human liver microsome (HLM) system. Swertia bimaculata showed significant inhibition on HCE 2 at 10 µg/mL among forty-nine kinds of TCMs. The extract of Swertia bimaculata was separated by preparative HPLC to afford demethylbellidifolin (1) identified by MS, 1H NMR, and 13C NMR spectra. Demethylbellidifolin (1) was assayed for its inhibitory HCE 2 effect by HCE 2-mediated DDAB hydrolysis, and its potential IC50 value was 3.12 ±â€¯0.64 µM. Demethylbellidifolin (1) was assigned as a mixed-type competitive inhibitor with the inhibiton constant Ki value of 6.87 µM by Lineweaver-Burk and slope plots. Living cell imaging was conducted to corroborate its inhibitory HCE 2 activity. Molecular docking indicated potential interactions of demethylbellidifolin (1) with HCE 2 through two hydrogen bonds of the C-3 and C-5 hydroxy groups with amino acid residues Glu227 and Ser228 in the catalytic cavity, respectively.

16.
Food Funct ; 10(7): 3839-3850, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31210195

RESUMO

Cholestatic liver injury induced by estrogen is a common clinical syndrome in women undergoing oral administration of contraceptives, pregnancy or hormone replacement therapy. Estrogen-induced cholestasis is associated with the accumulation of endogenous bile acids, which play critical roles in the disease progression and symptoms. In the present study, we described the protective effect of auraptene, a simple coumarin present in the peels of citrus fruits, such as grapefruit, against 17α-ethinylestradiol (EE)-induced cholestasis, and further elucidated the involvement of farnesoid X receptor (FXR) in the hepatoprotective effect. Auraptene treatment alleviated EE-induced cholestasis through increasing the bile flow and biliary bile acid output. The mechanism underlying the alleviated cholestasis by auraptene was associated with the increased efflux and inhibited hepatic uptake of bile acids via an induction of efflux transporters (Bsep and Mrp2) and downregulation of Ntcp. Furthermore, auraptene reduced the bile acid synthesis through repressing Cyp7a1 and Cyp8b1, and increased the bile acid metabolism through an induction in the gene expression of Sult2a1. The mentioned genes involved in the bile acid homeostasis were modulated by FXR. We further demonstrated that the changes in transporters and enzymes, as well as ameliorated liver histology by auraptene, were abrogated by the FXR antagonist guggulsterone. In conclusion, auraptene alleviated EE-induced cholestasis due to FXR-mediated gene regulation.


Assuntos
Colestase/tratamento farmacológico , Colestase/prevenção & controle , Citrus/química , Cumarínicos/farmacologia , Extratos Vegetais/farmacologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Ácidos e Sais Biliares/metabolismo , Doença Hepática Induzida por Substâncias e Drogas , Colestase/induzido quimicamente , Colesterol 7-alfa-Hidroxilase , Fígado/lesões , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Esteroide 12-alfa-Hidroxilase/metabolismo , Sulfotransferases/metabolismo , Simportadores/metabolismo
17.
Int J Biol Macromol ; 135: 1028-1033, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31163244

RESUMO

Laccase (LAC) belongs to the blue multi­copper lignolytic oxidase enzymes, and has been regarded as an important tool to produce some important dimers in the application of biotechnology. In this study, sixteen coumarins 1-16 were screened to investigate the catalytic ability of LAC, and three coumarins 6, 7, and 16 could be catalyzed to produce three coumarin derivative coupling with acetone 6a, 7a, and 16a. The potential interaction mechanisms of three coumarins 6, 7, and 16 with LAC were analyzed by molecular docking. The kinetic analyses of catalytic reactions for coumarins 6, 7, and 16 with LAC were performed by using the transformed products 6a, 7a, and 16a as standard substances. Km values of coumarins 6, 7, and 16 were ranged from 0.87 ±â€¯0.07 µM to 2.74 ±â€¯0.29 µM, respectively. This finding suggested that LAC was a reliable method to catalyze oxidative coupling.


Assuntos
Cumarínicos/química , Lacase/química , Acoplamento Oxidativo , Biotransformação , Catálise , Cinética , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Análise Espectral , Relação Estrutura-Atividade
18.
Toxicol Appl Pharmacol ; 371: 63-73, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30953615

RESUMO

Gambogic acid (GA), a major ingredient of Garcinia hanburryi, is known to have diverse biological effects. The present study was designed to evaluate the anti-fibrotic effects of GA on hepatic fibrosis and reveal its underlying mechanism. We investigated the anti-fibrotic effect of GA on dimethylnitrosamine and bile duct ligation induced liver fibrosis in rats in vivo. The rat and human hepatic stellate cell lines (HSCs) lines were chose to evaluate the effect of GA in vitro. Our results indicated that GA could significantly ameliorate liver fibrosis associated with improving serum markers, decrease in extracellular matrix accumulation and HSCs activation in vivo. GA significantly inhibited the proliferation of HSC cells and induced the cell cycle arrest at the G1 phase. Moreover, GA triggered autophagy at early time point and subsequent initiates mitochondrial mediated apoptotic pathway resulting in HSC cell death. The mechanism of GA was related to inhibit heat shock protein 90 (HSP90) and degradation of the client proteins inducing PI3K/AKT and MAPK signaling pathways inhibition. This study demonstrated that GA effectively ameliorated liver fibrosis in vitro and in vivo, which provided new insights into the application of GA for liver fibrosis.

19.
Int J Biol Macromol ; 133: 184-189, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30991064

RESUMO

As a part of our searching for natural human carboxylesterase 2 (human CES 2) inhibitors from traditional Chinese medicine, we found that the extract of Alisma orientale significantly inhibited human CES 2 in vitro. The investigation on A. orientale led to the isolation of a new protostane-type triterpenoid alismanin I (1). Its structure was determined according to HRESIMS, 1D and 2D NMR spectra. Alismanin I (1) displayed significantly inhibitory activity against human CES 2 with IC50 value of 1.31 ±â€¯0.09 µM assayed by human CES 2-mediated DDAB hydrolysis. According to its inhibition kinetic result, compound 1 was a noncompetitive type inhibitor, and its Ki was 3.65 µM. Its inhibitory effect was confirmed in living cell level through a visual manner. The potential interaction mechanism of compound 1 with human CES 2 was also analyzed by circular dichroism (CD) spectrum and molecular docking.


Assuntos
Alisma/química , Carboxilesterase/antagonistas & inibidores , Carboxilesterase/metabolismo , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Extratos Vegetais/farmacologia , Carboxilesterase/química , Domínio Catalítico , Dicroísmo Circular , Inibidores Enzimáticos/metabolismo , Humanos , Cinética , Extratos Vegetais/metabolismo
20.
Eur J Pharm Sci ; 133: 95-103, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30928510

RESUMO

Dicaffeoylquinic acids (DCQAs) are widely distributed in daily food and herb medicine (such as Dengzhanxiyin injection) with multiple health benefits and pharmacological activities. However, drug-drug Interactions (DDIs) between DCQAs and possible concomitant drugs were not fully understood in clinic. The purpose of present study was to investigate the role of organic anion transporters (OATs) in the transport of DCQAs and to explore the potential clinical DDIs using in vitro transporter assays. Uptake study using hOAT1/hOAT3-transfected HEK293 cells revealed that none of DCQAs was OAT1 substrate, while 3,4-DCQA, 3,5-DCQA, and 4,5-DCQA were substrates of OAT3 with Km values of 119.7 ±â€¯28.8, 269.3 ±â€¯129.5 and 53.2 ±â€¯32.1 µM, respectively. The docking analysis revealed that 3,4-DCQA, 3,5-DCQA, and 4,5-DCQA were effectively embedded in the active site of OAT3 and fitted well with the cavity in three-dimensional space. Moreover, the classical substrates/inhibitors of OAT decreased the accumulation of 3,4-DCQA, 3,5-DCQA, and 4,5-DCQA in kidney slices, suggesting potential DDI risks with co-administration of substrate drugs of OAT. In fact, antivirals, antibiotics, neuroprotective agents, and PPIs (proton pump inhibitors) all showed varying degrees of inhibition of OAT3-mediated uptake of 3,4-DCQA, 3,5-DCQA, and 4,5-DCQA in vitro. For cefaclor, ceftizoxime, pantoprazole, and zidovudine, in particular, their IC50 values were <10 times the maximal free plasma concentration, indicating potential clinically relevant DDIs when used together with DCQAs. These findings provided useful information for the prediction of DDIs between DCQAs and OAT3 inhibitors, and rational application of herbal medicines containing DCQAs in clinic.


Assuntos
Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Ácido Quínico/análogos & derivados , Animais , Transporte Biológico , Interações de Medicamentos , Células HEK293 , Humanos , Rim/metabolismo , Masculino , Proteína 1 Transportadora de Ânions Orgânicos/genética , Proteína 1 Transportadora de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/genética , Ácido Quínico/farmacologia , Ratos Sprague-Dawley
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