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1.
Chem Commun (Camb) ; 55(89): 13362-13365, 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31631195

RESUMO

Rule-of-five parameters and membrane permeabilities have been routinely used to guide development of orally bioavailabile drugs. Here we compare enantiomeric pairs of cyclic hexapeptides with identical rule-of-five parameters and membrane permeabilities. For each enantiomeric pair, the isomer with more l- than d-amino acids is much more orally bioavailable in rats, more metabolically stable to rat liver microsomes, and cleared more slowly in vivo.


Assuntos
Peptídeos Cíclicos/metabolismo , Peptídeos Cíclicos/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Conformação Molecular , Peptídeos Cíclicos/administração & dosagem , Ratos , Estereoisomerismo
2.
J Agric Food Chem ; 67(44): 12199-12207, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31595753

RESUMO

Salvianolic acid A (Sal A) has a wide range of pharmacological activities. To date, there have been no systematic and detailed metabolite research data of Sal A after oral administration in vitro and in vivo. In this study, a rapid and systematic method based on ultrafast liquid chromatography-quadrupole-time-of-flight mass spectrometry was developed to detect metabolites of Sal A in vitro (human liver microsome, human intestinal microbiota, artificial gastric, and intestinal juice) and in vivo (urine, plasma, feces, and various organs collected after oral administration of Sal A to normal rats and pseudo-germ-free rats). A total of 26 metabolites of Sal A were characterized. These metabolites were formed through extensive metabolic reactions, such as hydroxylation, hydrogenation, and glucuronidation reactions. This study provides novel possibility for exploring the potential biological mechanism of Sal A, and aids the promotion of clinical application.


Assuntos
Ácidos Cafeicos/química , Ácidos Cafeicos/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/metabolismo , Lactatos/química , Lactatos/metabolismo , Espectrometria de Massas/métodos , Salvia miltiorrhiza/química , Adulto , Animais , Feminino , Humanos , Masculino , Metaboloma , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Ratos , Ratos Sprague-Dawley , Adulto Jovem
3.
Zhongguo Zhong Yao Za Zhi ; 44(16): 3562-3568, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31602923

RESUMO

The mass spectrometry-based metabolomics method was used to systematically investigate the formation of celastrol metabolites,and the effect of celastrol on endogenous metabolites. The mice plasma,urine and feces samples were collected after oral administration of celastrol. Ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry( UPLC-QTOF-MS) was applied to analyze the exogenous metabolites of celastrol and its altered endogenous metabolites. Mass defect filtering was adopted to screen for the exogenous metabolites of celastrol. Multivariate statistical analysis was used to identify the endogenous metabolites affected by celastrol. Celastrol and its eight metabolites were detected in urine and feces of mice,and 5 metabolites of them were reported for the first time. The hydroxylated metabolites were observed in the metabolism of both human liver microsomes and mouse liver microsomes. Further recombinant enzyme experiments revealed CYP3 A4 was the major metabolic enzyme involved in the formation of hydroxylated metabolites. Urinary metabolomics revealed that celastrol can affect the excretion of intestinal bacteria-related endogenous metabolites,including hippuric acid,phenylacetylglycine,5-hydroxyindoleacetic acid,urocanic acid,cinnamoylglycine,phenylproplonylglycine and xanthurenic acid. These results are helpful to elucidate the metabolism and disposition of celastrol in vivo,and its mechanism of action.


Assuntos
Metabolômica , Triterpenos/farmacocinética , Animais , Cromatografia Líquida de Alta Pressão , Humanos , Espectrometria de Massas , Camundongos , Microssomos Hepáticos/metabolismo , Triterpenos/metabolismo
4.
Int J Nanomedicine ; 14: 7095-7106, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31564867

RESUMO

Background: Norisoboldine (NOR), the main isoquinoline alkaloid constituent in Radix Linderae, was demonstrated to have an outstanding anti-arthritis activity. However, a poor oral bioavailability of NOR creates a barrier for its development and application. Methods: A new self-nanoemulsifying drug delivery system (SNEDDS) loaded with the phospholipid complex (PC) was designed to improve the oral bioavailability of NOR. NOR-PC was prepared by solvent evaporation method with a mixture of phospholipid and NOR at a mass ratio of 3:1. The property of PC is to improve the liposolubility of NOR, and made PC embedded in the drug delivery system. The physicochemical property of NOR-PC was characterized by differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FT-IR). According to the ability to dissolve NOR-PC, the oil and cosurfactant were chosen. The surfactant was selected based on its emulsification efficiency in SNEDDS. Pseudo-ternary phase diagram was created to select the best formulation of NOR-PC-SNEDDS, and the pharmacokinetic parameters were detected in rats. In addition, intestinal lymphatic transport and liver microsome experiment were studied to gain insight into the mechanism for NOR-PC-SNEDDS increasing the oral bioavailability of NOR. Results: Solubility detection showed that the PC significantly improved the liposolubility of NOR. NOR-PC-SNEDDS was prepared using NOR-PC, Ethyl oleate, Labrasol, Cremophor EL and transcutol HP at a weight ratio of 1:2:3.36:2.24:2.4 (w/w/w/w/w). The particle size and zeta potential of NOR-PC-SNEDDS were 36.72±1.47 nm and -4.91±0.49 mV after dilution with distilled water at a ratio of 1:50 (w/w). The absolute bioavailability of NOR in the NOR-PC-SNEDDS group significantly increased and the value was 372% in relative to NOR group. Further studies indicated that NOR-PC-SNEDDS promoted the oral bioavailability of NOR by enhancing intestinal lymphatic absorption and inhibiting Phase II metabolism of NOR. Conclusion: These findings suggested that NOR-PC-SNEDDS was able to promote the oral bioavailability of NOR, which provided a foundation for the further development and application of NOR.


Assuntos
Absorção Fisiológica , Alcaloides/farmacologia , Sistemas de Liberação de Medicamentos , Emulsões/química , Nanopartículas/química , Fosfolipídeos/química , Administração Oral , Alcaloides/sangue , Alcaloides/química , Alcaloides/farmacocinética , Animais , Varredura Diferencial de Calorimetria , Intestinos/fisiologia , Sistema Linfático/fisiologia , Masculino , Desintoxicação Metabólica Fase II , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Transição de Fase , Ratos Sprague-Dawley , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Tensoativos/química , Termodinâmica , Fatores de Tempo
5.
J Agric Food Chem ; 67(45): 12481-12495, 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31630515

RESUMO

Biochanin A is a dietary isoflavone with multiple biological functions. Owing to a lack of comprehensive studies of biochanin A metabolism, this study was designed to further clarify the processes involved in biochanin A metabolism. In this study, ultrahigh-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS/MS) was utilized to characterize the metabolism of biochanin A in vivo and in vitro. As a result, 43 metabolites in rats, 22 metabolites in liver microsomes, and 18 metabolites in intestinal flora were elucidated, and 5 metabolites were identified by comparison with standards. Oxidation, demethylation, hydrogenation, internal hydrolysis, conjugation (e.g., glucuronidation, sulfonation, glucose conjugation, methylation, and acetylation), and their composite reactions were determined to be major processes involved in biochanin A biotransformation. The results contribute to a better understanding of the pharmacological mechanism of biochanin A and provide a basis for comprehension of the safety and toxicity of biochanin A.


Assuntos
Genisteína/metabolismo , Isoflavonas/metabolismo , Animais , Biotransformação , Cromatografia Líquida de Alta Pressão , Microbioma Gastrointestinal , Genisteína/química , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Isoflavonas/química , Masculino , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem
6.
Nat Biotechnol ; 37(9): 1038-1040, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31477924

RESUMO

We have developed a deep generative model, generative tensorial reinforcement learning (GENTRL), for de novo small-molecule design. GENTRL optimizes synthetic feasibility, novelty, and biological activity. We used GENTRL to discover potent inhibitors of discoidin domain receptor 1 (DDR1), a kinase target implicated in fibrosis and other diseases, in 21 days. Four compounds were active in biochemical assays, and two were validated in cell-based assays. One lead candidate was tested and demonstrated favorable pharmacokinetics in mice.


Assuntos
Aprendizado Profundo , Receptor com Domínio Discoidina 1/antagonistas & inibidores , Receptor com Domínio Discoidina 1/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Animais , Receptor com Domínio Discoidina 1/genética , Cães , Inibidores Enzimáticos , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Conformação Proteica , Ratos
7.
J Agric Food Chem ; 67(42): 11650-11656, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31554401

RESUMO

Occurring in hops (Humulus lupulus) and beer as a racemic mixture, (2R,2S)-8-prenylnaringenin (8-PN) is a potent phytoestrogen in hop dietary supplements used by women as alternatives to conventional hormone therapy. With a half-life exceeding 20 h, 8-PN is excreted primarily as 8-PN-7-O-glucuronide or 8-PN-4'-O-glucuronide. Human liver microsomes and 11 recombinant human UDP-glucuronosyltransferases (UGTs) were used to catalyze the formation of the two oxygen-linked glucuronides of purified (2R)-8-PN and (2S)-8-PN, which were subsequently identified using mass spectrometry and nuclear magnetic resonance spectroscopy. Formation of (2R)- and (2S)-8-PN-7-O-glucuronides predominated over the 8-PN-4'-O-glucuronides except for intestinal UGT1A10, which formed more (2S)-8-PN-4'-O-glucuronide. (2R)-8-PN was a better substrate for all 11 UGTs except for UGT1A1, which formed more of both (2S)-8-PN glucuronides than (2R)-8-PN glucuronides. Although several UGTs conjugated both enantiomers of 8-PN, some conjugated just one enantiomer, suggesting that human phenotypic variation might affect the routes of metabolism of this chiral estrogenic constituent of hops.


Assuntos
Flavanonas/química , Glucuronídeos/química , Glucuronosiltransferase/química , Extratos Vegetais/química , Biocatálise , Flavanonas/metabolismo , Glucuronídeos/metabolismo , Glucuronosiltransferase/metabolismo , Humanos , Humulus/química , Humulus/metabolismo , Espectrometria de Massas , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Extratos Vegetais/metabolismo , Estereoisomerismo
8.
Eur J Med Chem ; 182: 111589, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31425906

RESUMO

A series of aryl-substituted indole and indoline derivatives were discovered as novel RORγt agonists by a scaffold-based hybridization of the reported RORγt agonists 1 and 2. SAR studies on the core structures, the RHS hydrophilic side chains and the LHS hydrophobic aryl groups of a hybrid compound 3 led to the identification of potent RORγt agonists with improved drug-like properties. Compound 14 represented a high potency lead with an EC50 of 20.8 ±â€¯1.5 nM, the (S)-enantiomer (EC50 = 16.1 ±â€¯4.5 nM) of which was 17 times more potent than the (R) counterpart (EC50 = 286 ±â€¯30.4 nM) in RORγ dual FRET assay. The cell-based GAL4 reporter gene assay also suggested 14 as the most active compound which exhibited an EC50 of 247 ±â€¯33.1 nM and a maximum activation percentage of 133%. Moreover, 14 showed high metabolic stability (t1/2 = 113 min) in mouse liver microsome and had improved aqueous solubility at pH 7.4 compared to the parent compounds. Furthermore, 14 was found to be orally bioavailable and demonstrated excellent in vivo pharmacokinetics in mice. Present studies indicate that 14 deserves further investigation in tumor animal models as a potential candidate of RORγt agonist for cancer immunotherapy.


Assuntos
Descoberta de Drogas , Indóis/farmacologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Animais , Relação Dose-Resposta a Droga , Humanos , Interações Hidrofóbicas e Hidrofílicas , Indóis/síntese química , Indóis/química , Camundongos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Relação Estrutura-Atividade
9.
J Mass Spectrom ; 54(9): 738-749, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31368246

RESUMO

Black pepper, though commonly employed as a spice, has many medicinal properties. It consists of volatile oils, alkaloids, pungent resins, etc., of which piperine is a major constituent. Though safe at low doses, piperine causes alteration in the activity of drug metabolising enzymes and transporters at high dose and is known to precipitate liver toxicity. It has a potential to form reactive metabolite(s) (RM) owing to the presence of structural alerts, such as methylenedioxyphenyl (MDP), α, ß-unsaturated carbonyl group (Michael acceptor), and piperidine. The present study was designed to detect and characterize stable and RM(s) of piperine formed on in vitro incubation with human liver microsomes. The investigation of RMs was done with the aid of trapping agents, viz, glutathione (GSH) and N-acetylcysteine (NAC). The samples were analysed by ultra-high performance liquid chromatography coupled with high resolution mass spectrometry (UHPLC-HRMS) using Thermo Scientific Q Exactive Plus Orbitrap. Full scan MS followed by data-dependent MS2 (Full MS-ddMS2 ) mode was used to establish mass spectrometric fragmentation pathways of protonated piperine and its metabolites. In total, four stable metabolites and their isomers (M1a-c, M2a-b, M3a-c, and M4a-b) were detected. Their formation involved removal of carbon (3, M1a-c), hydroxylation (2, M2a-b), hydroxylation with hydrogenation (3, M3a-c), and dehydrogenation (2, M4a-b). Out of these metabolites, M1, M2, and M3 are reported earlier in the literature, but their isomers and two M4 variants are novel. In addition, six novel conjugates of RMs, including three GSH conjugates of m/z 579 and three NAC conjugates of m/z 435, were also observed.


Assuntos
Alcaloides/análise , Alcaloides/metabolismo , Benzodioxóis/análise , Benzodioxóis/metabolismo , Microssomos Hepáticos/metabolismo , Piperidinas/análise , Piperidinas/metabolismo , Alcamidas Poli-Insaturadas/análise , Alcamidas Poli-Insaturadas/metabolismo , Acetilcisteína/química , Cromatografia Líquida de Alta Pressão , Glutationa/química , Humanos , Isomerismo , Espectrometria de Massas em Tandem
10.
Life Sci ; 234: 116770, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31421085

RESUMO

Aim Licoricidin has multiple pharmacological activities. The present study was designed to investigate the permeability and pharmacokinetic behavior of licoricidin using in vitro models. MATERIAL AND METHODS: First, human liver microsomes and recombinant human supersomes were used to investigate the interactions between metabolic enzymes and licoricidin. In addition, rat, minipig, rabbit, dog, monkey, and human liver microsomes were used to determine metabolic differences among species. The parallel artificial membrane permeability assay (PAMPA) was used to explore licoricidin permeability behavior. KEY FINDINGS: At 100 µM, licoricidin strongly inhibited CYP2C9, CYP2C19, CYP3A4, UGT1A3, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT2B4, UGT2B7, UGT2B15, and UGT2B17. Licoricidin metabolism exhibited considerable differences among species; dog, pig, and rat liver microsomes showed higher metabolic capacity than the other species. Seven licoricidin metabolites were identified by liquid chromatography-tandem mass spectrometry, and hydration and hydroxylation were the major metabolic pathways. The PAMPA permeability of licoricidin was moderate at both pH 4.0 and 7.4. SIGNIFICANCE: The present study will support further pharmacological or toxicological research on licoricidin.


Assuntos
Benzopiranos/metabolismo , Benzopiranos/farmacocinética , Animais , Inibidores das Enzimas do Citocromo P-450/metabolismo , Inibidores das Enzimas do Citocromo P-450/farmacocinética , Sistema Enzimático do Citocromo P-450/metabolismo , Cães , Glucuronosiltransferase/antagonistas & inibidores , Glucuronosiltransferase/metabolismo , Haplorrinos , Humanos , Redes e Vias Metabólicas , Microssomos Hepáticos/metabolismo , Permeabilidade , Coelhos , Ratos , Especificidade da Espécie , Suínos , Porco Miniatura
11.
Chem Pharm Bull (Tokyo) ; 67(7): 699-706, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257325

RESUMO

In our search for novel orally active α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists, we found that conversion of an allyl group in the lead compound 2-[allyl(4-methylphenyl)amino]-4H-pyrido[3,2-e][1,3]thiazin-4-one (4) to a 2-cyanoethyl group significantly increased inhibitory activity against AMPA receptor-mediated kainate-induced toxicity in rat hippocampal cultures. Here, we synthesized 10 analogs bearing a 2-cyanoethyl group and administered them to mice to evaluate their anticonvulsant activity in maximal electroshock (MES)- and pentylenetetrazol (PTZ)-induced seizure tests, and their effects on motor coordination in a rotarod test. 3-{(4-Oxo-4H-pyrido[3,2-e][1,3]thiazin-2-yl)[4-(trifluoromethoxy)phenyl]amino}propanenitrile (25) and 3-[(2,2-difluoro-2H-1,3-benzodioxol-5-yl)(4-oxo-4H-pyrido[3,2-e][1,3]thiazin-2-yl)amino]propanenitrile (27) exhibited potent anticonvulsant activity in both seizure tests and induced minor motor disturbances as indicated in the rotarod test. The protective index values of 25 and 27 for MES-induced seizures (10.7 and 12.0, respectively) and PTZ-induced seizures (6.0 and 5.6, respectively) were considerably higher compared with those of YM928 (5) and talampanel (1).


Assuntos
Anticonvulsivantes/síntese química , Nitrilos/química , Receptores de AMPA/antagonistas & inibidores , Administração Oral , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Microssomos Hepáticos/metabolismo , Nitrilos/farmacologia , Nitrilos/uso terapêutico , Pentilenotetrazol/toxicidade , Ratos , Ratos Wistar , Receptores de AMPA/metabolismo , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Convulsões/veterinária , Relação Estrutura-Atividade
12.
Eur J Med Chem ; 179: 502-514, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276895

RESUMO

Inhibition of BET family of bromodomain is an appealing intervention strategy for several cancers and inflammatory diseases. This article highlights our work toward the identification of potent, selective, and efficacious BET inhibitors using a structure-based approach focused on improving potency. Our medicinal chemistry efforts led to the identification of compound 24, a novel phenanthridin-6(5H)-one derivative, as a potent (IC50 = 0.24 µM) and selective BET inhibitor with excellent cancer cell lines inhibitory activities and favorable oral pharmacokinetic properties.


Assuntos
Antineoplásicos/farmacologia , Desenho de Drogas , Proteínas Nucleares/antagonistas & inibidores , Fenantridinas/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Feminino , Humanos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Proteínas Nucleares/metabolismo , Fenantridinas/administração & dosagem , Fenantridinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismo
13.
Eur J Med Chem ; 180: 72-85, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31301565

RESUMO

A series of pyrazole-thiophene derivatives exhibiting good Akt inhibitory activities were obtained on the basis of conformational restriction strategy, leading to the discovery of compound 1d and 1o which showed excellent in vitro antitumor effect against a variety of hematologic cancer cells and their potential of inducing apoptosis, blocking the cell cycles at S phase and significantly inhibiting the phosphorylation of downstream biomarkers of Akt kinase of cancer cells. Amongst, compound 1o also exhibited good PK profiles and inhibited about 40% tumor growth in MM1S xenograft model. Compound 1o might be a potential candidate for further development.


Assuntos
Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Pirazóis/farmacologia , Tiofenos/farmacologia , Administração Oral , Animais , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HCT116 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirazóis/administração & dosagem , Pirazóis/química , Relação Estrutura-Atividade , Tiofenos/administração & dosagem , Tiofenos/química , Células Tumorais Cultivadas
14.
Chem Biol Interact ; 310: 108744, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31299239

RESUMO

The epidemic of loperamide abuse and misuse in the patients for the alternative to opioids has become an increasing worldwide concern and has led to considerations about the potential for drug-drug interactions between loperamide and other combined drugs, especially inhibitors of cytochrome P450 (CYP450) enzymes, such as axitinib. This study assessed the effects of axitinib on the metabolism of loperamide and its main metabolite N-demethylated loperamide in rats and in rat liver microsomes (RLM), human liver microsomes (HLM) and recombinant human CYP3A4*1. The concentrations of both compounds were determined by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The exposures (AUC(0-t), AUC(0-∞) and Cmax) of loperamide and N-demethylated loperamide showed a conspicuous increase when loperamide was co-administered with axitinib. The Tmax of loperamide increased while CLz/F decreased under the influence of axitinib. In vitro, axitinib inhibited loperamide metabolism with the IC50 of 18.34 µM for RLM, 1.705 µM for HLM and 1.604 µM for CYP3A4*1, and it was confirmed as a non-competitive inhibitor in all enzymes. Taken together, the results indicated that axitinib had an obvious inhibitory impact on loperamide metabolism both in vivo and in vitro. Thus, more attention should be paid to the concurrent use of loperamide and axitinib to reduce the risk of unexpected clinical outcomes.


Assuntos
Axitinibe/farmacologia , Loperamida/farmacocinética , Animais , Cromatografia Líquida de Alta Pressão , Citocromo P-450 CYP3A/metabolismo , Desmetilação , Interações de Medicamentos , Humanos , Loperamida/antagonistas & inibidores , Loperamida/metabolismo , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Ratos , Espectrometria de Massas em Tandem
15.
Chem Biol Interact ; 310: 108745, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31299240

RESUMO

Ursodeoxycholic acid (UDCA) is a major effective constituent of bear bile powder, which is widely used as function food in China and is documented in the Chinese pharmacopoeia as a traditional Chinese medicine. UDCA has been developed as the only accepted therapy by the US FDA for primary biliary cholangitis. Recently, the US FDA granted accelerated approval to obeticholic acid (OCA), a semisynthetic bile acid derivative from chenodeoxycholic acid, for primary biliary cholangitis. However, some perplexing toxicities of UDCA have been reported in the clinic. The present work aimed to investigate the difference between UDCA and OCA in regard to potential metabolic activation through acyl glucuronidation and hepatic accumulation of consequent acyl glucuronides. Our results demonstrated that the metabolic fates of UDCA and OCA were similar. Both UDCA and OCA were predominantly metabolically activated by conjugation to the acyl glucuronide in human liver microsomes. UGT1A3 played a predominant role in the carboxyl glucuronidation of both UDCA and OCA, while UGT2B7 played a major role in their hydroxyl glucuronidation. Further uptake studies revealed that OATP1B1- and 1B3-transfected cells could selectively uptake UDCA acyl glucuronide, but not UDCA, OCA, and OCA acyl glucuronide. In summary, the liver disposition of OCA is different from that of UDCA due to hepatic uptake, and liver accumulation of UDCA acyl glucuronide might be related to the perplexing toxicities of UDCA.


Assuntos
Ácido Quenodesoxicólico/análogos & derivados , Glucuronídeos/metabolismo , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Microssomos Hepáticos/metabolismo , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo , Ácido Ursodesoxicólico/metabolismo , Animais , Transporte Biológico , Ácido Quenodesoxicólico/metabolismo , Humanos , Medicina Tradicional Chinesa , Ursidae , Ácido Ursodesoxicólico/análogos & derivados , Ácido Ursodesoxicólico/toxicidade
16.
Anal Bioanal Chem ; 411(16): 3561-3579, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31183523

RESUMO

As synthetic cannabinoids are extensively metabolized, there is an urgent need for data on which metabolites can be used for successful urine screening. This study examines the in vitro metabolism of EG-018 and its 5F-analogue EG-2201 by means of comparing three different in vitro models: pooled human liver microsomes, cytochrome P450 isoenzymes, and a fungal approach utilizing the filamentous fungus Cunninghamella elegans LENDNER, which is known for its ability to mimic human biotransformation of xenobiotics. In addition, this study includes the screening of two authentic urine samples from individuals with proven EG-018 consumption, for the evaluation of in vitro-in vivo extrapolations made in the study. Incubation with pooled human liver microsomes yielded 15 metabolites of EG-018 belonging to six different metabolite subgroups, and 21 metabolites of EG-2201 belonging to seven different metabolite subgroups, respectively. Incubation with cytochrome P450 isoenzymes incubation yielded a further three EG-018 and five EG-2201 metabolites. With reference to their summed metabolite peak abundancies, the isoenzymes CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 were shown to contribute most to the microsomal metabolism of EG-018 and EG-2201. CYP2B6 was shown to make the lowest contribution, by far. As the phase I metabolism of both synthetic cannabinoids was shown to be distributed over a substantial number of different cytochrome P450 isoenzymes, it was concluded that it is likely to not be significantly affected by co-consumption of other drugs. Although fungal incubation with Cunninghamella elegans yielded an additional three EG-018 and four EG-2201 metabolites not observed after microsomal incubation, metabolites generated by Cunninghamella elegans were in good correlation with those generated by microsomal incubations. The fungal model demonstrated its ability to be an independent in vitro model in synthetic cannabinoid metabolism research. The three tested in vitro models enable sufficient predictive in vitro-in vivo extrapolations, comparable to those obtained from hepatocyte incubation published in the literature. In addition, with regard to the screening of authentic urine samples and comparison with the literature, one monohydroxylated EG-018 metabolite and two monohydroxylated EG-2201 metabolites can be recommended as urinary targets, on the basis of the tested in vitro models. Graphical abstract.


Assuntos
Canabinoides/metabolismo , Cunninghamella/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Isoenzimas/metabolismo , Microssomos Hepáticos/metabolismo , Canabinoides/urina , Cromatografia Líquida/métodos , Humanos , Espectrometria de Massas em Tandem/métodos
17.
Chem Biol Interact ; 308: 288-293, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31150629

RESUMO

Hypaconitine is an active and highly toxic constituent derived from Aconitum species. Here we aimed to determine the chronotoxicity of hypaconitine in mice, and to investigate a potential role of metabolism in hypaconitine chronotoxicity. Cardiac toxicity was assessed by measuring CK (creatine kinase) and LDH (lactate dehydrogenase) levels after hypaconitine administration to wild-type and Bmal1-/- (a clock disrupted model) mice at different times of day. The mRNA and protein levels of Cyp3a11 in mouse livers were determined by qPCR and western blotting, respectively. In vitro metabolism was assessed using liver microsomes. Pharmacokinetic study of hypaconitine was performed with wild-type mice. We observed injection time-dependent toxicity (i.e., a more severe toxicity during the light phase than the dark phase) for hypaconitine in mice. The chronotoxicity was attributed to a difference in systemic exposure of hypaconitine caused by time of day-dependent metabolism. Furthermore, circadian metabolism of hypaconitine was accounted for by the diurnal expression of Cyp3a11, a major enzyme for hypaconitine detoxification in the liver. Moreover, Bmal1 ablation in mice abolished the daily rhythm of Cyp3a11 expression and abrogated the time-dependency of hypaconitine toxicity. In conclusion, circadian Cyp3a11 metabolism contributed to chronotoxicity of hypaconitine in mice. This metabolism-based chronotoxicity would facilitate the formulation of best timing for drug administration.


Assuntos
Aconitina/análogos & derivados , Relógios Circadianos , Citocromo P-450 CYP3A/metabolismo , Fígado/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Fatores de Transcrição ARNTL/deficiência , Fatores de Transcrição ARNTL/genética , Aconitina/metabolismo , Aconitina/farmacocinética , Aconitina/toxicidade , Animais , Creatina Quinase/sangue , Citocromo P-450 CYP3A/genética , Células HEK293 , Meia-Vida , Humanos , Fígado/metabolismo , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microssomos Hepáticos/metabolismo , RNA Mensageiro/metabolismo
18.
Phytother Res ; 33(7): 1770-1783, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31155811

RESUMO

N-acetyl-p-benzoquinoneimine (NAPQI) is toxic metabolite of paracetamol formed primarily by cytochrome P4502E1 (CYP2E1) metabolic pathway when administered at therapeutic doses or overdose. The influence of quercetin (flavonoid) on the bioactivation of paracetamol to NAPQI was investigated using rat liver microsomes and rats in vivo. Paracetamol (80 mg/kg) was administered orally without or with silymarin (100 mg/kg), a known inhibitor of CYP2E1, CYP3A4 and quercetin (10 and 20 mg/kg) to rats for 15 consecutive days. Area under the plasma concentration-time curve (AUC0-∞ ) and the peakplasma concentration (Cmax ) of paracetamol were dose-dependently increased with quercetin (10 and 20 mg/kg) compared to paracetamol control group (p < 0.001). On the other hand, the AUC0-∞ and Cmax of NAPQI were decreased significantly with quercetin. The same results were observed with silymarin also. The elevated liver and kidney functional enzymes/compounds were significantly reduced by quercetin and silymarin compared to paracetamol control group. The formation of NAPQI was reduced in the incubation samples in presence of quercetin in experiment using isolated rat hepatocytes. The presentstudy results revealed that quercetin might be inhibited the CYP2E1-mediated metabolism of paracetamol; thereby decreased the formation of NAPQI and protected the liver and kidney.


Assuntos
Acetaminofen/farmacocinética , Benzoquinonas/metabolismo , Hepatócitos/efeitos dos fármacos , Iminas/metabolismo , Quercetina/farmacologia , Acetaminofen/sangue , Animais , Células Cultivadas , Citocromo P-450 CYP2E1/metabolismo , Inibidores do Citocromo P-450 CYP2E1/farmacologia , Hepatócitos/metabolismo , Rim/metabolismo , Fígado/metabolismo , Masculino , Microssomos Hepáticos/metabolismo , Ratos Wistar , Silimarina/farmacologia
19.
Food Chem Toxicol ; 131: 110542, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31163218

RESUMO

S-equol, an active metabolite of the soy isoflavone daidzein, is mainly metabolized into glucuronide(s) by UDP-glucuronosyltransferase (UGT) enzymes in mammals. In the present study, S-equol glucuronidation was examined in the liver and intestinal microsomes of humans, monkeys, dogs, rats, and mice using a kinetic analysis. CLint values for 7- and 4'-glucuronidation by liver microsomes were higher than those by intestinal microsomes in all species. CLint values for total glucuronidation (sum of 7- and 4'-glucuronidation) were rats (7.6) > monkeys (5.8) > mice (4.9) > dogs (2.8) > humans (1.0) for liver microsomes, and rats (9.6) > mice (2.8) > dogs (1.3) ≥ monkeys (1.2) > humans (1.0) for intestinal microsomes, respectively. Regarding regioselective glucuronidation by liver and intestinal microsomes, CLint values were 7-glucuronidation > 4'-glucuronidation for humans, monkeys, dogs, and mice, and 4'-glucuronidation > 7-glucuronidation for rats. These results suggest that the metabolic abilities of UGT enzymes toward S-equol in the liver and intestines markedly differ among humans, monkeys, dogs, rats, and mice.


Assuntos
Equol/metabolismo , Glucuronídeos/biossíntese , Microssomos Hepáticos/metabolismo , Adolescente , Adulto , Idoso , Animais , Criança , Pré-Escolar , Cães , Equol/química , Glucuronosiltransferase/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Cinética , Macaca fascicularis , Camundongos , Pessoa de Meia-Idade , Ratos Sprague-Dawley , Estereoisomerismo , Adulto Jovem
20.
Exp Parasitol ; 204: 107718, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31201779

RESUMO

The aim of the current work was to evaluate a potential pharmacokinetic interaction between the flukicide triclabendazole (TCBZ) and the broad-spectrum benzimidazole (BZD) anthelmintic oxfendazole (OFZ) in sheep. To this end, both an in vitro assay in microsomal fractions and an in vivo trial in lambs parasitized with Haemonchus contortus resistant to OFZ and its reduced derivative fenbendazole (FBZ) were carried out. Sheep microsomal fractions were incubated together with OFZ, FBZ, TCBZ, or a combination of either FBZ and TCBZ or OFZ and TCBZ. OFZ production was significantly diminished upon coincubation of FBZ and TCBZ, whereas neither FBZ nor OFZ affected the S-oxidation of TCBZ towards its sulfoxide and sulfone metabolites. For the in vivo trial, lambs were treated with OFZ (Vermox® oral drench at a single dose of 5 mg/kg PO), TCBZ (Fasinex® oral drench at a single dose of 12 mg/kg PO) or both compounds at a single dose of 5 (Vermox®) and 12 mg/kg (Fasinex®) PO. Blood samples were taken to quantify drug and metabolite concentrations, and pharmacokinetic parameters were calculated by means of non-compartmental analysis. Results showed that the pharmacokinetic parameters of active molecules and metabolites were not significantly altered upon coadministration. The sole exception was the increase in the mean residence time (MRT) of OFZ and FBZ sulfone upon coadministration, with no significant changes in the remaining pharmacokinetic parameters. This research is a further contribution to the study of metabolic drug-drug interactions that may affect anthelmintic efficacies in ruminants.


Assuntos
Anti-Helmínticos/farmacocinética , Benzimidazóis/farmacocinética , Triclabendazol/farmacocinética , Animais , Anti-Helmínticos/metabolismo , Área Sob a Curva , Benzimidazóis/metabolismo , Biotransformação , Sistema Enzimático do Citocromo P-450/metabolismo , Interações de Medicamentos , Fenbendazol/metabolismo , Fígado/metabolismo , Masculino , Microssomos Hepáticos/metabolismo , Oxigenases/metabolismo , Ovinos , Triclabendazol/metabolismo
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