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1.
J Med Chem ; 66(15): 10381-10412, 2023 08 10.
Article in English | MEDLINE | ID: mdl-37489798

ABSTRACT

Because of the wide use of Fingolimod for the treatment of multiple sclerosis (MS) and its cardiovascular side effects such as bradycardia, second-generation sphingosine 1-phosphate receptor 1 (S1P1) agonist drugs for MS have been developed and approved by FDA. The issue of bradycardia is still present with the new drugs, however, which necessitates further exploration of S1P1 agonists with improved safety profiles for next-generation MS drugs. Herein, we report a tetrahydroisoquinoline or a benzo[c]azepine core-based S1P1 agonists such as 32 and 60 after systematic examination of hydrophilic groups and cores. We investigated the binding modes of our representative compounds and their molecular interactions with S1P1 employing recent S1P1 cryo-EM structures. Also, favorable ADME properties of our compounds were shown. Furthermore, in vivo efficacy of our compounds was clearly demonstrated with PLC and EAE studies. Also, the preliminary in vitro cardiovascular safety of our compound was verified with human iPSC-derived cardiomyocytes.


Subject(s)
Multiple Sclerosis , Tetrahydroisoquinolines , Humans , Multiple Sclerosis/drug therapy , Multiple Sclerosis/metabolism , Sphingosine-1-Phosphate Receptors , Bradycardia/chemically induced , Receptors, Lysosphingolipid/agonists , Receptors, Lysosphingolipid/metabolism , Receptors, Lysosphingolipid/therapeutic use , Fingolimod Hydrochloride/pharmacology , Fingolimod Hydrochloride/therapeutic use , Tetrahydroisoquinolines/therapeutic use , Sphingosine/metabolism
3.
Pharmaceutics ; 13(2)2021 Jan 28.
Article in English | MEDLINE | ID: mdl-33525442

ABSTRACT

Acacetin, an important ingredient of acacia honey and a component of several medicinal plants, exhibits therapeutic effects such as antioxidative, anticancer, anti-inflammatory, and anti-plasmodial activities. However, to date, studies reporting a systematic investigation of the in vivo fate of orally administered acacetin are limited. Moreover, the in vitro physicochemical and biopharmaceutical properties of acacetin in the gastrointestinal (GI) tract and their pharmacokinetic impacts remain unclear. Therefore, in this study, we aimed to systematically investigate the oral absorption and disposition of acacetin using relevant rat models. Acacetin exhibited poor solubility (≤119 ng/mL) and relatively low stability (27.5-62.0% remaining after 24 h) in pH 7 phosphate buffer and simulated GI fluids. A major portion (97.1%) of the initially injected acacetin dose remained unabsorbed in the jejunal segments, and the oral bioavailability of acacetin was very low at 2.34%. The systemic metabolism of acacetin occurred ubiquitously in various tissues (particularly in the liver, where it occurred most extensively), resulting in very high total plasma clearance of 199 ± 36 mL/min/kg. Collectively, the poor oral bioavailability of acacetin could be attributed mainly to its poor solubility and low GI luminal stability.

4.
Commun Biol ; 4(1): 5, 2021 01 04.
Article in English | MEDLINE | ID: mdl-33398110

ABSTRACT

Previous work has revealed that progerin-lamin A binding inhibitor (JH4) can ameliorate pathological features of Hutchinson-Gilford progeria syndrome (HGPS) such as nuclear deformation, growth suppression in patient's cells, and very short life span in an in vivo mouse model. Despite its favorable effects, JH4 is rapidly eliminated in in vivo pharmacokinetic (PK) analysis. Thus, we improved its property through chemical modification and obtained an optimized drug candidate, Progerinin (SLC-D011). This chemical can extend the life span of LmnaG609G/G609G mouse for about 10 weeks and increase its body weight. Progerinin can also extend the life span of LmnaG609G/+ mouse for about 14 weeks via oral administration, whereas treatment with lonafarnib (farnesyl-transferase inhibitor) can only extend the life span of LmnaG609G/+ mouse for about two weeks. In addition, progerinin can induce histological and physiological improvement in LmnaG609G/+ mouse. These results indicate that progerinin is a strong drug candidate for HGPS.


Subject(s)
Progeria/drug therapy , Adolescent , Animals , Child , Disease Models, Animal , Drug Evaluation, Preclinical , Female , HEK293 Cells , Humans , Lamin Type A/antagonists & inhibitors , Male , Mice , Primary Cell Culture
5.
Bioorg Med Chem Lett ; 29(16): 2275-2282, 2019 08 15.
Article in English | MEDLINE | ID: mdl-31253533

ABSTRACT

As a potential treatment of type 2 diabetes, a novel PPARγ non-TZD full agonist, compound 18 (BR102375) was identified from the original lead BR101549 by the SAR efforts of the labile metabolite control through bioisosteres approach. In vitro assessments of BR102375 demonstrated its activating potential of PPARγ comparable to Pioglitazone as well as the induction of related gene expressions. Further in vivo evaluation of BR102375 in diabetic rodent models successfully proved its glucose lowering effect as a potential antidiabetic agent, but the anticipated suppression of weight gain was not evident. The X-ray co-crystal analysis of BR102375-PPARγ LBD unexpectedly revealed binding modes totally different from those of BR101549, which was found, instead, closely resembled to those of TZD full agonists.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Drug Discovery , Hypoglycemic Agents/pharmacology , Oxadiazoles/pharmacology , PPAR gamma/agonists , Crystallography, X-Ray , Diabetes Mellitus, Type 2/metabolism , Dose-Response Relationship, Drug , Humans , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/chemistry , Models, Molecular , Molecular Structure , Oxadiazoles/chemistry , PPAR gamma/metabolism , Structure-Activity Relationship
6.
Bioorg Med Chem ; 26(15): 4382-4389, 2018 08 15.
Article in English | MEDLINE | ID: mdl-30054191

ABSTRACT

In this study, we designed and synthesized several novel "Y"-shaped biaryl PPARδ agonists. Structure-activity relationship (SAR) studies demonstrated that compound 3a was the most active agonist with an EC50 of 2.6 nM. We also synthesized and evaluated enantiospecific R and S isomers of compound 3a to confirm that R isomer (EC50 = 0.7 nM) shows much more potent activity than S isomer (EC50 = 6.1 nM). Molecular docking studies between the PPAR ligand binding domain and enantiospecific R and S isomers of compound 3a were performed. In vitro absorption, distribution, metabolism, excretion, and toxicity (ADMET) and in vivo PK profiles show that compound 3a possesses superior drug-like properties including good bioavailability. Our overall results clearly demonstrate that this orally administrable PPARδ agonist 3a is a viable drug candidate for the treatment of various PPARδ-related disorders.


Subject(s)
Acetates/chemistry , Biphenyl Compounds/chemical synthesis , PPAR delta/agonists , Acetates/chemical synthesis , Acetates/pharmacokinetics , Administration, Oral , Animals , Binding Sites , Biphenyl Compounds/chemistry , Biphenyl Compounds/pharmacology , Crystallography, X-Ray , Drug Design , Half-Life , Humans , Inhibitory Concentration 50 , Mice , Microsomes/metabolism , Molecular Docking Simulation , PPAR delta/metabolism , Protein Structure, Tertiary , Rats , Stereoisomerism , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/metabolism
7.
Int J Toxicol ; 37(5): 393-403, 2018.
Article in English | MEDLINE | ID: mdl-29923436

ABSTRACT

Predicting drug-drug interactions (DDIs) is an important step during drug development to avoid unexpected side effects. Cytochrome P450 (CYP) 3A4 is the most abundant human hepatic phase I enzyme, which metabolizes >50% of therapeutic drugs. Therefore, it is essential to test the potential of a drug candidate to induce CYP3A4 expression or inhibit its activity. Recently, 3-dimensional (3-D) mammalian cell culture models have been adopted in drug discovery research to assess toxicity, DDIs, and pharmacokinetics. In this study, we applied a human 3-D spheroid culture protocol using HepaRG cells combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to assess its ability to predict CYP3A4 inhibition. Levels of midazolam, a specific substrate of CYP3A4, were used to determine the long-term metabolic capacity of CYP3A4. Midazolam was decreased in the 3-D HepaRG culture system by ∼80% over 7 days, whereas its primary metabolite, 1-hydroxymidazolam, increased by ∼40%. Next, we assessed hepatotoxicity by determining the cytotoxicity of known hepatotoxicants in HepaRG spheroids, HepG2 cells, and primary human hepatocytes. Significant differences in cytotoxicity were detected in the system using 3-D HepaRG spheroids. These results suggest that 3-D HepaRG spheroids are a good model for prediction of CYP inhibition and hepatotoxicity in screening of early drug candidates.


Subject(s)
Chemical and Drug Induced Liver Injury , Cytochrome P-450 CYP3A Inhibitors/pharmacology , Cytochrome P-450 CYP3A/metabolism , Spheroids, Cellular/drug effects , Cell Culture Techniques , Cell Survival/drug effects , Cytochrome P-450 CYP3A/genetics , Hep G2 Cells , Humans
8.
Biomed Chromatogr ; 31(2)2017 Feb.
Article in English | MEDLINE | ID: mdl-27432781

ABSTRACT

Anacetrapib is a potent and selective CETP inhibitor and is undergoing phase III clinical trials for the treatment of dyslipidemia. A simple and sensitive high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for the quantification of anacetrapib in rat plasma was developed and validated using an easily purchasable compound, chlorpropamide, as an internal standard (IS). A minimal volume of rat plasma sample (20 µL) was prepared by a single-step deproteinization procedure with 80 µL of acetonitrile. Chromatographic separation was performed using Kinetex C18 column with a gradient mobile phase consisting of water and acetonitrile containing 0.1% formic acid at a flow rate of 0.3 mL/min. Mass spectrometric detection was performed using selected reaction monitoring modes at the mass/charge transitions m/z 638 → 283 for anacetrapib and m/z 277 → 175 for IS. The assay was validated to demonstrate the selectivity, linearity, precision, accuracy, recovery, matrix effect and stability. The lower limit of quantification was 5 ng/mL. This LC-MS/MS assay was successfully applied in the rat plasma protein binding and pharmacokinetic studies of anacetrapib. The fraction of unbound anacetrapib was determined to be low (ranging from 5.66 to 12.3%), and the absolute oral bioavailability of anacetrapib was 32.7%.


Subject(s)
Anticholesteremic Agents/blood , Chromatography, High Pressure Liquid/methods , Oxazolidinones/blood , Tandem Mass Spectrometry/methods , Animals , Anticholesteremic Agents/metabolism , Biological Availability , Limit of Detection , Male , Oxazolidinones/metabolism , Protein Binding , Rats , Rats, Sprague-Dawley , Reproducibility of Results
9.
Arch Pharm Res ; 38(5): 725-33, 2015.
Article in English | MEDLINE | ID: mdl-25052955

ABSTRACT

Cytochrome P450 (CYP) is an important enzyme that can act on xenobiotic substances such as toxic chemicals or drugs. Phenobarbital (PB) has been widely used to induce CYP2B activity to investigate the drug-drug interaction of CYP2B substrate drugs. Leelamine is a diterpene compound, and is the current focus of efforts to develop a treatment for diabetes. In this study, we identified the selective and potent inductive effect of leelamine on CYP2B at doses of 5, 10, or 20 mg/kg in male ICR mice for 1 or 3 days. In liver, the activity of CYP2B significantly increased 3.6-fold after treatment with leelamine, compared to vehicle-treated group. Activities of benzyloxyresorufin O-dealkylase and pentoxyresorufin O-dealkylase significantly increased 6.3- and 5.3-fold, respectively, with a single treatment of 20 mg/kg leelamine for 1 day. Furthermore, immunoblot analysis showed that significantly and dose-dependently increased CYP2B10 protein levels in liver. However, PCR results showed that there were no significant changes in the CAR and CYP2B mRNA levels after leelamine treatment. Accordingly, we suggest that leelamine is a novel substitute of PB for the selective induction of CYP2B activity in vivo.


Subject(s)
Cytochrome P-450 CYP2B1/biosynthesis , Diterpenes/chemistry , Diterpenes/pharmacology , Liver/drug effects , Liver/enzymology , Animals , Body Weight/drug effects , Body Weight/physiology , Cytochrome P-450 Enzyme Inducers/chemistry , Cytochrome P-450 Enzyme Inducers/pharmacology , Dose-Response Relationship, Drug , Enzyme Activation/drug effects , Enzyme Activation/physiology , Enzyme Induction/drug effects , Enzyme Induction/physiology , Male , Mice , Mice, Inbred ICR
10.
Biopharm Drug Dispos ; 36(3): 163-73, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25451157

ABSTRACT

GSK5182 (4-[(Z)-1-[4-(2-dimethylaminoethyloxy)phenyl]-hydroxy-2-phenylpent-1-enyl]phenol) is a specific inverse agonist for estrogen-related receptor γ, a member of the orphan nuclear receptor family that has important functions in development and homeostasis. This study was performed to elucidate the metabolites of GSK5182 and to characterize the enzymes involved in its metabolism. Incubation of human liver microsomes with GSK5182 in the presence of NADPH resulted in the formation of three metabolites, M1, M2 and M3. M1 and M3 were identified as N-desmethyl-GSK5182 and GSK5182 N-oxide, respectively, on the basis of liquid chromatography-tandem mass spectrometric (LC-MS/MS) analysis. M2 was suggested to be hydroxy-GSK5182 through interpretation of its MS/MS fragmentation pattern. In addition, the specific cytochrome P450 (P450) and flavin-containing monooxygenase (FMO) isoforms responsible for GSK5182 oxidation to the three metabolites were identified using a combination of correlation analysis, chemical inhibition in human liver microsomes and metabolism by expressed recombinant P450 and FMO isoforms. GSK5182 N-demethylation and hydroxylation is mainly mediated by CYP3A4, whereas FMO1 and FMO3 contribute to the formation of GSK5182 N-oxide from GSK5182. The present data will be useful for understanding the pharmacokinetics and drug interactions of GSK5182 in vivo.


Subject(s)
Estrogens/pharmacology , Hypoglycemic Agents/pharmacology , Microsomes, Liver/metabolism , Tamoxifen/analogs & derivatives , Cytochrome P-450 Enzyme Inhibitors/pharmacology , Cytochrome P-450 Enzyme System/metabolism , Humans , Receptors, Estrogen/metabolism , Recombinant Proteins/metabolism , Tamoxifen/pharmacology
11.
Biopharm Drug Dispos ; 36(4): 258-64, 2015 May.
Article in English | MEDLINE | ID: mdl-25522350

ABSTRACT

Non-steroidal anti-inflammatory drugs (NSAIDs) are used widely to relieve pain and to decrease inflammation. Several clinical studies have reported that NSAIDs inhibit uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes. Therefore, the study evaluated the inhibitory potential of 15 NSAIDs on the activities of six UGT isoforms (i.e. UGT1A1, 1A3, 1A4, 1A6, 1A9 and 2B7) in human liver microsomes (HLMs). Among the 15 NSAIDs tested here, mefenamic acid and diclofenac inhibited all UGTs tested in this study. Piroxicam and niflumic acid inhibited UGT1A9 activity (IC50 = 73.8 µm and 0.38 µm, respectively) and naproxen selectively inhibited UGT2B7 activity (IC50 = 53.1 µm), whereas it did not inhibit the other UGTs tested (IC50 > 200 µm). Diflunisal inhibited the UGT1A1 (IC50 = 33.0 µm) and UGT1A9 (IC50 = 19.4 µm). Acetaminophen, fenoprofen, ibuprofen, ketoprofen, meloxicam, phenylbutazone, salicylic acid and sulindac showed negligible inhibitory effects on the six UGTs (IC50 > 100 µm). These results suggest that some NSAIDs have the potential to inhibit UGTs in vitro.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Glucuronosyltransferase/antagonists & inhibitors , Chromatography, Liquid , Humans , Isoenzymes/antagonists & inhibitors , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Tandem Mass Spectrometry
12.
Rapid Commun Mass Spectrom ; 28(22): 2405-14, 2014 Nov 30.
Article in English | MEDLINE | ID: mdl-25303469

ABSTRACT

RATIONALE: Uridine 5'-diphosphoglucuronosyltransferase (UGT) enzymes are essential for the clearance of many drugs; however, altered UGT activity is a potential cause of adverse drug-drug interactions (DDI). The early detection of potential DDI is an important aspect of drug discovery that has led to the development of new screening methods for drug interactions. We developed a screening method for the simultaneous evaluation of six human liver UGT enzyme activites using in vitro cocktail incubation and tandem mass spectrometry. METHODS: The two in vitro cocktail doses were developed to minimize drug interactions among substrates. The method is based on liquid chromatography/tandem mass spectrometry (LC/MS/MS). Electrospray ionization (ESI) in both positive and negative modes was used to quantify the metabolites and the diagnostic loss of the glucuronosyl moiety to form the aglycone product was estimated using the selected reaction monitoring (SRM) mode. RESULTS: The method was validated by comparing inhibition data obtained from the incubation of each individual probe substrate alone with data from the cocktail method. The intra- and inter-day accuracy and precision data for the six UGT metabolites ranged from 92.2 to 100.3% and less than 15.2%, respectively. The IC(50) values showed no significant differences between individual and cocktail incubations. CONCLUSIONS: As a screening technique for inhibitory interactions of these six human liver UGT enzymes, this method will be useful for advancing mechanistic understanding of drug interactions.


Subject(s)
Chromatography, Liquid/methods , Glucuronosyltransferase/analysis , Glucuronosyltransferase/metabolism , Microsomes, Liver/enzymology , Tandem Mass Spectrometry/methods , Humans , Least-Squares Analysis , Reproducibility of Results , Sensitivity and Specificity
13.
Antimicrob Agents Chemother ; 57(11): 5448-56, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23959307

ABSTRACT

Albendazole and fenbendazole are broad-spectrum anthelmintics that undergo extensive metabolism to form hydroxyl and sulfoxide metabolites. Although CYP3A and flavin-containing monooxygenase have been implicated in sulfoxide metabolite formation, the enzymes responsible for hydroxyl metabolite formation have not been identified. In this study, we used human liver microsomes and recombinant cytochrome P450s (P450s) to characterize the enzymes involved in the formation of hydroxyalbendazole and hydroxyfenbendazole from albendazole and fenbendazole, respectively. Of the 10 recombinant P450s, CYP2J2 and/or CYP2C19 was the predominant enzyme catalyzing the hydroxylation of albendazole and fenbendazole. Albendazole hydroxylation to hydroxyalbendazole is primarily mediated by CYP2J2 (0.34 µl/min/pmol P450, which is a rate 3.9- and 8.1-fold higher than the rates for CYP2C19 and CYP2E1, respectively), whereas CYP2C19 and CYP2J2 contributed to the formation of hydroxyfenbendazole from fenbendazole (2.68 and 1.94 µl/min/pmol P450 for CYP2C19 and CYP2J2, respectively, which are rates 11.7- and 8.4-fold higher than the rate for CYP2D6). Correlation analysis between the known P450 enzyme activities and the rate of hydroxyalbendazole and hydroxyfenbendazole formation in samples from 14 human liver microsomes showed that albendazole hydroxylation correlates with CYP2J2 activity and fenbendazole hydroxylation correlates with CYP2C19 and CYP2J2 activities. These findings were supported by a P450 isoform-selective inhibition study in human liver microsomes. In conclusion, our data for the first time suggest that albendazole hydroxylation is primarily catalyzed by CYP2J2, whereas fenbendazole hydroxylation is preferentially catalyzed by CYP2C19 and CYP2J2. The present data will be useful in understanding the pharmacokinetics and drug interactions of albendazole and fenbendazole in vivo.


Subject(s)
Albendazole/metabolism , Anthelmintics/metabolism , Aryl Hydrocarbon Hydroxylases/metabolism , Cytochrome P-450 Enzyme System/metabolism , Fenbendazole/metabolism , Microsomes, Liver/enzymology , Aryl Hydrocarbon Hydroxylases/antagonists & inhibitors , Aryl Hydrocarbon Hydroxylases/genetics , Biotransformation , Cytochrome P-450 CYP2C19 , Cytochrome P-450 CYP2J2 , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/genetics , Enzyme Assays , Enzyme Inhibitors/pharmacology , Humans , Hydroxylation , Kinetics , Liver/enzymology , Recombinant Proteins/genetics , Recombinant Proteins/metabolism
14.
Biopharm Drug Dispos ; 34(4): 195-202, 2013 May.
Article in English | MEDLINE | ID: mdl-23446989

ABSTRACT

Obovatol, a major constituent of the leaves of Magnolia obovata Thunb, is known to inhibit nuclear factor-κB activity and arachidonic acid-induced platelet aggregation. This study was performed to identify the metabolites of obovatol in human liver microsomes. Human liver microsomes incubated with obovatol in the presence of NADPH and/or UDPGA resulted in the formation of six metabolites, M1-M6. M1 and M2 were identified as hydroxyobovatol, on the basis of liquid chromatography/tandem mass spectrometric (LC-MS/MS) analysis. M1, M2 and obovatol were further metabolized to their glucuronide conjugates, obovatol-glucuronide (M3), obovatol-diglucuronide (M4) and hydroxyobovatol-glucuronide (M5 and M6). The inhibitory potency of obovatol on eight major human P450s was also investigated in human liver microsomes. In these experiments, obovatol strongly inhibited CYP2C19-mediated S-mephenytoin hydroxylase activity with an IC(50) value of 0.8 µM, which could have implications for drug-drug interactions.


Subject(s)
Cytochrome P-450 Enzyme System/drug effects , Microsomes, Liver/enzymology , Phenyl Ethers/pharmacology , Aryl Hydrocarbon Hydroxylases/metabolism , Chromatography, Liquid , Cytochrome P-450 CYP2C19 , Cytochrome P-450 Enzyme System/metabolism , Humans , Inhibitory Concentration 50 , Magnolia/chemistry , NADP/metabolism , Phenyl Ethers/administration & dosage , Phenyl Ethers/metabolism , Tandem Mass Spectrometry , Uridine Diphosphate Glucuronic Acid/metabolism
15.
J Microbiol Biotechnol ; 22(12): 1659-64, 2012 Dec.
Article in English | MEDLINE | ID: mdl-23221528

ABSTRACT

TSAHC [4'-(p-toluenesulfonylamido)-4-hydroxychalcone] is a promising antitumorigenic chalcone compound, especially against TM4SF5 (four-transmembrane L6 family member 5)-mediated hepatocarcinoma. We evaluated the potential of TSAHC to inhibit the catalytic activities of nine cytochrome P450 isoforms and of P-glycoprotein (Pgp). The abilities of TSAHC to inhibit phenacetin Odeethylation (CYP1A2), coumarin 6-hydroxylation (CYP2A6), bupropion hydroxylation (CYP2B6), amodiaquine Ndeethylation (CYP2C8), diclofenac 4-hydroxylation (CYP2C9), omeprazole 5-hydroxylation (CYP2C19), dextromethorphan O-demethylation (CYP2D6), chlorzoxazone 6-hydroxylation (CYP2E1), and midazolam 1'-hydroxylation (CYP3A) were tested using human liver microsomes. The P-gp inhibitory effect of TSAHC was assessed by [3H]digoxin accumulation in the LLCPK1-MDR1 cell system. TSAHC strongly inhibited CYP2C8, CYP2C9, and CYP2C19 isoform activities with Ki values of 0.81, 0.076, and 3.45 microM, respectively. It also enhanced digoxin accumulation in a dose-dependent manner in the LLCPK1-MDR1 cells. These findings indicate that TSAHC has the potential to inhibit CYP2C isoforms and P-gp activities in vitro. TSAHC might be used as a nonspecific inhibitor of CYP2C isoforms based on its negligible inhibitory effect on other P450 isoforms such as CYP1A2, CYP2A6, CYP2B6, CYP2D6, CYP2E1, and CYP3A.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Chalcone/analogs & derivatives , Cytochrome P-450 Enzyme System/metabolism , Microsomes, Liver/drug effects , Sulfonamides/pharmacology , Chalcone/pharmacology , Digoxin/metabolism , Drug Interactions , Humans , Microsomes, Liver/metabolism , Models, Biological
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