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1.
Proc Natl Acad Sci U S A ; 121(7): e2315069121, 2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38315851

RESUMO

A key step in drug discovery, common to many disease areas, is preclinical demonstration of efficacy in a mouse model of disease. However, this demonstration and its translation to the clinic can be impeded by mouse-specific pathways of drug metabolism. Here, we show that a mouse line extensively humanized for the cytochrome P450 gene superfamily ("8HUM") can circumvent these problems. The pharmacokinetics, metabolite profiles, and magnitude of drug-drug interactions of a test set of approved medicines were in much closer alignment with clinical observations than in wild-type mice. Infection with Mycobacterium tuberculosis, Leishmania donovani, and Trypanosoma cruzi was well tolerated in 8HUM, permitting efficacy assessment. During such assessments, mouse-specific metabolic liabilities were bypassed while the impact of clinically relevant active metabolites and DDI on efficacy were well captured. Removal of species differences in metabolism by replacement of wild-type mice with 8HUM therefore reduces compound attrition while improving clinical translation, accelerating drug discovery.


Assuntos
Doenças Transmissíveis , Descoberta de Drogas , Camundongos , Animais , Interações Medicamentosas , Modelos Animais de Doenças , Sistema Enzimático do Citocromo P-450/metabolismo , Aceleração
2.
J Med Chem ; 66(15): 10413-10431, 2023 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-37506194

RESUMO

There is an urgent need for new treatments for Chagas disease, a parasitic infection which mostly impacts South and Central America. We previously reported on the discovery of GSK3494245/DDD01305143, a preclinical candidate for visceral leishmaniasis which acted through inhibition of the Leishmania proteasome. A related analogue, active against Trypanosoma cruzi, showed suboptimal efficacy in an animal model of Chagas disease, so alternative proteasome inhibitors were investigated. Screening a library of phenotypically active analogues against the T. cruzi proteasome identified an active, selective pyridazinone, the development of which is described herein. We obtained a cryo-EM co-structure of proteasome and a key inhibitor and used this to drive optimization of the compounds. Alongside this, optimization of the absorption, distribution, metabolism, and excretion (ADME) properties afforded a suitable compound for mouse efficacy studies. The outcome of these studies is discussed, alongside future plans to further understand the series and its potential to deliver a new treatment for Chagas disease.


Assuntos
Doença de Chagas , Leishmaniose Visceral , Tripanossomicidas , Trypanosoma cruzi , Camundongos , Animais , Inibidores de Proteassoma/farmacologia , Inibidores de Proteassoma/uso terapêutico , Complexo de Endopeptidases do Proteassoma , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Leishmaniose Visceral/tratamento farmacológico , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico , Tripanossomicidas/química
3.
Eur J Med Chem ; 238: 114421, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35594652

RESUMO

Approximately 6-7 million people around the world are estimated to be infected with Trypanosoma cruzi, the causative agent of Chagas disease. The current treatments are inadequate and therefore new medical interventions are urgently needed. In this paper we describe the identification of a series of disubstituted piperazines which shows good potency against the target parasite but is hampered by poor metabolic stability. We outline the strategies used to mitigate this issue such as lowering logD, bioisosteric replacements of the metabolically labile piperazine ring and use of plate-based arrays for quick diversity scoping. We discuss the success of these strategies within the context of this series and highlight the challenges faced in phenotypic programs when attempting to improve the pharmacokinetic profile of compounds whilst maintaining potency against the desired target.


Assuntos
Doença de Chagas , Trypanosoma cruzi , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Humanos , Piperazinas/farmacologia
4.
RSC Med Chem ; 11(10): 1168-1177, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33479621

RESUMO

Visceral leishmaniasis (VL) affects millions of people across the world, largely in developing nations. It is fatal if left untreated and the current treatments are inadequate. As such, there is an urgent need for new, improved medicines. In this paper, we describe the identification of a 6-amino-N-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine scaffold and its optimization to give compounds which showed efficacy when orally dosed in a mouse model of VL.

5.
Proc Natl Acad Sci U S A ; 116(19): 9318-9323, 2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-30962368

RESUMO

Visceral leishmaniasis (VL), caused by the protozoan parasites Leishmania donovani and Leishmania infantum, is one of the major parasitic diseases worldwide. There is an urgent need for new drugs to treat VL, because current therapies are unfit for purpose in a resource-poor setting. Here, we describe the development of a preclinical drug candidate, GSK3494245/DDD01305143/compound 8, with potential to treat this neglected tropical disease. The compound series was discovered by repurposing hits from a screen against the related parasite Trypanosoma cruzi Subsequent optimization of the chemical series resulted in the development of a potent cidal compound with activity against a range of clinically relevant L. donovani and L. infantum isolates. Compound 8 demonstrates promising pharmacokinetic properties and impressive in vivo efficacy in our mouse model of infection comparable with those of the current oral antileishmanial miltefosine. Detailed mode of action studies confirm that this compound acts principally by inhibition of the chymotrypsin-like activity catalyzed by the ß5 subunit of the L. donovani proteasome. High-resolution cryo-EM structures of apo and compound 8-bound Leishmania tarentolae 20S proteasome reveal a previously undiscovered inhibitor site that lies between the ß4 and ß5 proteasome subunits. This induced pocket exploits ß4 residues that are divergent between humans and kinetoplastid parasites and is consistent with all of our experimental and mutagenesis data. As a result of these comprehensive studies and due to a favorable developability and safety profile, compound 8 is being advanced toward human clinical trials.


Assuntos
Antiprotozoários/administração & dosagem , Leishmania donovani/efeitos dos fármacos , Leishmania infantum/efeitos dos fármacos , Leishmaniose Visceral/diagnóstico por imagem , Inibidores de Proteassoma/administração & dosagem , Proteínas de Protozoários/antagonistas & inibidores , Animais , Antiprotozoários/química , Sítios de Ligação , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Leishmania donovani/química , Leishmania donovani/enzimologia , Leishmania infantum/química , Leishmania infantum/enzimologia , Leishmaniose Visceral/parasitologia , Masculino , Camundongos , Complexo de Endopeptidases do Proteassoma/química , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/química , Conformação Proteica , Proteínas de Protozoários/química , Proteínas de Protozoários/metabolismo
6.
ACS Med Chem Lett ; 10(3): 341-347, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30891137

RESUMO

In order to study the role of S1PRs in inflammatory skin disease, S1PR modulators are dosed orally and topically in animal models of disease. The topical application of S1PR modulators in these models may, however, lead to systemic drug concentrations, which can complicate interpretation of the observed effects. We set out to design soft drug S1PR modulators as topical tool compounds to overcome this limitation. A fast follower approach starting from the drug ponesimod allowed the rapid development of an active phenolic series of soft drugs. The phenols were, however, chemically unstable. Protecting the phenol as an ester removed the instability and provided a compound that is converted by enzymatic hydrolysis in the skin to the phenolic soft drug species. In simple formulations, topical dosing of these S1PR modulators to mice led to micromolar skin concentrations but no detectable blood concentrations. These topical tools will allow researchers to investigate the role of S1PR in skin, without involvement of systemic S1PR biology.

7.
Proc Natl Acad Sci U S A ; 116(14): 7015-7020, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30894487

RESUMO

Malaria and cryptosporidiosis, caused by apicomplexan parasites, remain major drivers of global child mortality. New drugs for the treatment of malaria and cryptosporidiosis, in particular, are of high priority; however, there are few chemically validated targets. The natural product cladosporin is active against blood- and liver-stage Plasmodium falciparum and Cryptosporidium parvum in cell-culture studies. Target deconvolution in P. falciparum has shown that cladosporin inhibits lysyl-tRNA synthetase (PfKRS1). Here, we report the identification of a series of selective inhibitors of apicomplexan KRSs. Following a biochemical screen, a small-molecule hit was identified and then optimized by using a structure-based approach, supported by structures of both PfKRS1 and C. parvum KRS (CpKRS). In vivo proof of concept was established in an SCID mouse model of malaria, after oral administration (ED90 = 1.5 mg/kg, once a day for 4 d). Furthermore, we successfully identified an opportunity for pathogen hopping based on the structural homology between PfKRS1 and CpKRS. This series of compounds inhibit CpKRS and C. parvum and Cryptosporidium hominis in culture, and our lead compound shows oral efficacy in two cryptosporidiosis mouse models. X-ray crystallography and molecular dynamics simulations have provided a model to rationalize the selectivity of our compounds for PfKRS1 and CpKRS vs. (human) HsKRS. Our work validates apicomplexan KRSs as promising targets for the development of drugs for malaria and cryptosporidiosis.


Assuntos
Criptosporidiose , Cryptosporidium parvum/enzimologia , Inibidores Enzimáticos/farmacologia , Lisina-tRNA Ligase/antagonistas & inibidores , Malária Falciparum , Plasmodium falciparum/enzimologia , Proteínas de Protozoários/antagonistas & inibidores , Animais , Criptosporidiose/tratamento farmacológico , Criptosporidiose/enzimologia , Modelos Animais de Doenças , Inibidores Enzimáticos/química , Humanos , Lisina-tRNA Ligase/metabolismo , Malária Falciparum/tratamento farmacológico , Malária Falciparum/enzimologia , Camundongos SCID , Proteínas de Protozoários/metabolismo
8.
J Med Chem ; 62(3): 1180-1202, 2019 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-30570265

RESUMO

The leishmaniases are diseases that affect millions of people across the world, in particular visceral leishmaniasis (VL) which is fatal unless treated. Current standard of care for VL suffers from multiple issues and there is a limited pipeline of new candidate drugs. As such, there is a clear unmet medical need to identify new treatments. This paper describes the optimization of a phenotypic hit against Leishmania donovani, the major causative organism of VL. The key challenges were to balance solubility and metabolic stability while maintaining potency. Herein, strategies to address these shortcomings and enhance efficacy are discussed, culminating in the discovery of preclinical development candidate GSK3186899/DDD853651 (1) for VL.


Assuntos
Leishmaniose Visceral/tratamento farmacológico , Morfolinas/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Tripanossomicidas/uso terapêutico , Animais , Feminino , Células Hep G2 , Humanos , Leishmania donovani/efeitos dos fármacos , Masculino , Camundongos Endogâmicos BALB C , Estrutura Molecular , Morfolinas/síntese química , Morfolinas/toxicidade , Testes de Sensibilidade Parasitária , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/toxicidade , Pirazóis/síntese química , Pirazóis/toxicidade , Pirimidinas/síntese química , Pirimidinas/toxicidade , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/toxicidade
9.
Bioorg Med Chem Lett ; 28(19): 3255-3259, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-30143424

RESUMO

The oral S1PR1 agonist ponesimod demonstrated substantial efficacy in a phase II clinical trial of psoriasis. Unfortunately, systemic side effects were observed, which included lymphopenia and transient bradycardia. We sought to develop a topical soft-drug S1PR1 agonist with an improved therapeutic index. By modifying ponesimod, we discovered an ester series of S1PR agonists. To increase metabolic instability in plasma we synthesised esters described as specific substrates for paraoxonase and butyrylcholinesterases, esterases present in human plasma.


Assuntos
Descoberta de Drogas , Receptores de Lisoesfingolipídeo/efeitos dos fármacos , Tiazóis/farmacologia , Administração Tópica , Arildialquilfosfatase/sangue , Cromatografia Líquida de Alta Pressão , Cromatografia de Fase Reversa , Esterases/sangue , Esterases/metabolismo , Humanos , Pele/enzimologia , Solubilidade , Receptores de Esfingosina-1-Fosfato , Relação Estrutura-Atividade , Tiazóis/administração & dosagem
10.
J Med Chem ; 61(15): 6592-6608, 2018 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-29944372

RESUMO

With the emergence of multidrug-resistant strains of Mycobacterium tuberculosis there is a pressing need for new oral drugs with novel mechanisms of action. Herein, we describe the identification of a novel morpholino-thiophenes (MOT) series following phenotypic screening of the Eli Lilly corporate library against M. tuberculosis strain H37Rv. The design, synthesis, and structure-activity relationships of a range of analogues around the confirmed actives are described. Optimized leads with potent whole cell activity against H37Rv, no cytotoxicity flags, and in vivo efficacy in an acute murine model of infection are described. Mode-of-action studies suggest that the novel scaffold targets QcrB, a subunit of the menaquinol cytochrome c oxidoreductase, part of the bc1-aa3-type cytochrome c oxidase complex that is responsible for driving oxygen-dependent respiration.


Assuntos
Citocromos c/metabolismo , Morfolinas/química , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Oxirredutases/metabolismo , Tiofenos/química , Tiofenos/farmacologia , Animais , Antituberculosos/química , Antituberculosos/farmacocinética , Antituberculosos/farmacologia , Antituberculosos/toxicidade , Chlorocebus aethiops , Camundongos , Relação Estrutura-Atividade , Tiofenos/farmacocinética , Tiofenos/toxicidade , Células Vero
11.
ACS Infect Dis ; 4(6): 954-969, 2018 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-29522317

RESUMO

Mycobacterium tuberculosis ( MTb) possesses two nonproton pumping type II NADH dehydrogenase (NDH-2) enzymes which are predicted to be jointly essential for respiratory metabolism. Furthermore, the structure of a closely related bacterial NDH-2 has been reported recently, allowing for the structure-based design of small-molecule inhibitors. Herein, we disclose MTb whole-cell structure-activity relationships (SARs) for a series of 2-mercapto-quinazolinones which target the ndh encoded NDH-2 with nanomolar potencies. The compounds were inactivated by glutathione-dependent adduct formation as well as quinazolinone oxidation in microsomes. Pharmacokinetic studies demonstrated modest bioavailability and compound exposures. Resistance to the compounds in MTb was conferred by promoter mutations in the alternative nonessential NDH-2 encoded by ndhA in MTb. Bioenergetic analyses revealed a decrease in oxygen consumption rates in response to inhibitor in cells in which membrane potential was uncoupled from ATP production, while inverted membrane vesicles showed mercapto-quinazolinone-dependent inhibition of ATP production when NADH was the electron donor to the respiratory chain. Enzyme kinetic studies further demonstrated noncompetitive inhibition, suggesting binding of this scaffold to an allosteric site. In summary, while the initial MTb SAR showed limited improvement in potency, these results, combined with structural information on the bacterial protein, will aid in the future discovery of new and improved NDH-2 inhibitors.


Assuntos
Mycobacterium tuberculosis/enzimologia , NADH Desidrogenase/química , Quinazolinonas/química , Estrutura Molecular , NADH Desidrogenase/antagonistas & inibidores , Quinazolinonas/síntese química , Quinazolinonas/farmacologia , Relação Estrutura-Atividade
12.
J Med Chem ; 60(17): 7284-7299, 2017 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-28844141

RESUMO

Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi, is the most common cause of cardiac-related deaths in endemic regions of Latin America. There is an urgent need for new safer treatments because current standard therapeutic options, benznidazole and nifurtimox, have significant side effects and are only effective in the acute phase of the infection with limited efficacy in the chronic phase. Phenotypic high content screening against the intracellular parasite in infected VERO cells was used to identify a novel hit series of 5-amino-1,2,3-triazole-4-carboxamides (ATC). Optimization of the ATC series gave improvements in potency, aqueous solubility, and metabolic stability, which combined to give significant improvements in oral exposure. Mitigation of a potential Ames and hERG liability ultimately led to two promising compounds, one of which demonstrated significant suppression of parasite burden in a mouse model of Chagas' disease.


Assuntos
Doença de Chagas/tratamento farmacológico , Triazóis/química , Triazóis/uso terapêutico , Tripanossomicidas/química , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi/efeitos dos fármacos , Aminação , Animais , Doença de Chagas/parasitologia , Chlorocebus aethiops , Descoberta de Drogas , Feminino , Humanos , Camundongos , Relação Estrutura-Atividade , Triazóis/farmacocinética , Triazóis/farmacologia , Tripanossomicidas/farmacocinética , Tripanossomicidas/farmacologia , Células Vero
13.
Drug Metab Dispos ; 42(12): 2023-32, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25217486

RESUMO

Cerlapirdine (SAM-531, PF-05212365) is a selective, potent, full antagonist of the 5-hydroxytryptamine 6 (5-HT6) receptor. Cerlapirdine and other 5-HT6 receptor antagonists have been in clinical development for the symptomatic treatment of Alzheimer's disease. A human absorption, distribution, metabolism, and excretion study was conducted to gain further understanding of the metabolism and disposition of cerlapirdine. Because of the low amount of radioactivity administered, total (14)C content and metabolic profiles in plasma, urine, and feces were determined using accelerator mass spectrometry (AMS). After a single, oral 5-mg dose of [(14)C]cerlapirdine (177 nCi), recovery of total (14)C was almost complete, with feces being the major route of elimination of the administered dose, whereas urinary excretion played a lesser role. The extent of absorption was estimated to be at least 70%. Metabolite profiling in pooled plasma samples showed that unchanged cerlapirdine was the major drug-related component in circulation, representing 51% of total (14)C exposure in plasma. One metabolite (M1, desmethylcerlapirdine) was detected in plasma, and represented 9% of the total (14)C exposure. In vitro cytochrome P450 reaction phenotyping studies showed that M1 was formed primarily by CYP2C8 and CYP3A4. In pooled urine samples, three major drug-related peaks were detected, corresponding to cerlapirdine-N-oxide (M3), cerlapirdine, and desmethylcerlapirdine. In feces, cerlapirdine was the major (14)C component excreted, followed by desmethylcerlapirdine. The results of this study demonstrate that the use of the AMS technique enables comprehensive quantitative elucidation of the disposition and metabolic profiles of compounds administered at a low radioactive dose.


Assuntos
Radioisótopos de Carbono/metabolismo , Indazóis/metabolismo , Metaboloma/fisiologia , Sulfonas/metabolismo , Administração Oral , Adulto , Sistema Enzimático do Citocromo P-450/metabolismo , Fezes/química , Humanos , Masculino , Espectrometria de Massas/métodos , Taxa de Depuração Metabólica/fisiologia , Metabolômica/métodos , Pessoa de Meia-Idade , Receptores de Serotonina/metabolismo , Serotonina/metabolismo , Adulto Jovem
14.
Eur J Pharm Sci ; 43(3): 141-50, 2011 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-21540108

RESUMO

A clinical study was conducted to assess the ability of a microdose (100 µg) to predict the human pharmacokinetics (PK) following a therapeutic dose of clarithromycin, sumatriptan, propafenone, paracetamol (acetaminophen) and phenobarbital, both within the study and by reference to the existing literature on these compounds and to explore the source of any nonlinearity if seen. For each drug, 6 healthy male volunteers were dosed with 100 µg (14)C-labelled compound. For clarithromycin, sumatriptan, and propafenone this labelled dose was administered alone, i.e. as a microdose, orally and intravenously (iv) and as an iv tracer dose concomitantly with an oral non-labelled therapeutic dose, in a 3-way cross over design. The oral therapeutic doses were 250, 50, and 150 mg, respectively. Paracetamol was given as the labelled microdose orally and iv using a 2-way cross over design, whereas phenobarbital was given only as the microdose orally. Plasma concentrations of total (14)C and parent drug were measured using accelerator mass spectrometry (AMS) or HPLC followed by AMS. Plasma concentrations following non-(14)C-labelled oral therapeutic doses were measured using either HPLC-electrochemical detection (clarithromycin) or HPLC-UV (sumatriptan, propafenone). For all five drugs an oral microdose predicted reasonably well the PK, including the shape of the plasma profile, following an oral therapeutic dose. For clarithromycin, sumatriptan, and propafenone, one parameter, oral bioavailability, was marginally outside of the normally acceptable 2-fold prediction interval around the mean therapeutic dose value. For clarithromycin, sumatriptan and propafenone, data obtained from an oral and iv microdose were compared within the same cohort of subjects used in the study, as well as those reported in the literature. For paracetamol (oral and iv) and phenobarbital (oral), microdose data were compared with those reported in the literature only. Where 100 µg iv (14)C-doses were given alone and with an oral non-labelled therapeutic dose, excellent accord between the PK parameters was observed indicating that the disposition kinetics of the drugs tested were unaffected by the presence of therapeutic concentrations. This observation implies that any deviation from linearity following the oral therapeutic doses occurs during the absorption process.


Assuntos
Acetaminofen , Claritromicina , Fenobarbital , Propafenona , Sumatriptana , Acetaminofen/administração & dosagem , Acetaminofen/sangue , Acetaminofen/farmacocinética , Administração Oral , Adolescente , Adulto , Área Sob a Curva , Radioisótopos de Carbono/administração & dosagem , Radioisótopos de Carbono/sangue , Radioisótopos de Carbono/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Claritromicina/administração & dosagem , Claritromicina/sangue , Claritromicina/farmacocinética , Estudos Cross-Over , Relação Dose-Resposta a Droga , Humanos , Injeções Intravenosas , Masculino , Espectrometria de Massas/métodos , Pessoa de Meia-Idade , Fenobarbital/administração & dosagem , Fenobarbital/sangue , Fenobarbital/farmacocinética , Propafenona/administração & dosagem , Propafenona/sangue , Propafenona/farmacocinética , Sumatriptana/administração & dosagem , Sumatriptana/sangue , Sumatriptana/farmacocinética
15.
Eur J Pharm Sci ; 40(2): 125-31, 2010 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-20307657

RESUMO

A human pharmacokinetic study was performed to assess the ability of a microdose to predict the pharmacokinetics of a therapeutic dose of fexofenadine and to determine its absolute oral bioavailability. Fexofenadine was chosen to represent an unmetabolized transporter substrate (P-gP and OATP). Fexofenadine was administered to 6 healthy male volunteers in a three way cross-over design. A microdose (100microg) of (14)C-drug was administered orally (period 1) and intravenously by 30min infusion (period 2). In period 3 an intravenous tracer dose (100microg) of (14)C-drug was administered simultaneously with an oral unlabelled therapeutic dose (120mg). Plasma was collected from all 3 periods and analysed for both total (14)C content and parent drug by accelerator mass spectrometry (AMS). For period 3, plasma samples were also analysed using HPLC-fluorescence to determine total drug concentration. Urine was collected and analysed for total (14)C. Good concordance between the microdose and therapeutic dose pharmacokinetics was observed. Microdose: CL 13L/h, CL(R) 4.1L/h, V(ss) 54L, t(1/2) 16h; therapeutic dose: CL 16L/h, CL(R) 6.2L/h, V(ss) 64L, t(1/2) 12h. The absolute oral bioavailability of fexofenadine was 0.35 (microdose 0.41, therapeutic dose 0.30). Despite a 1200-fold difference in dose of fexofenadine, the microdose predicted well the pharmacokinetic parameters following a therapeutic dose for this transporter dependent compound.


Assuntos
Antialérgicos/farmacocinética , Terfenadina/análogos & derivados , Administração Oral , Adolescente , Adulto , Antialérgicos/administração & dosagem , Antialérgicos/sangue , Área Sob a Curva , Disponibilidade Biológica , Estudos Cross-Over , Relação Dose-Resposta a Droga , Meia-Vida , Humanos , Masculino , Pessoa de Meia-Idade , Terfenadina/administração & dosagem , Terfenadina/sangue , Terfenadina/farmacocinética , Adulto Jovem
16.
J Agric Food Chem ; 54(5): 1906-13, 2006 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-16506852

RESUMO

Tea catechins have been shown to reduce plasma cholesterol and suppress hypertriacylglycerolemia by reducing triglyceride absorption. However, the mechanism is not yet clear. One of the possible mechanisms is that tea polyphenols may modify dietary fat emulsification in the gastrointestinal tract. The digestive enzyme (lipase) acts on specific emulsion interface properties (droplet size and surface area). Therefore, changes in these properties may modify emulsification and lead to changes in dietary fat digestion and absorption. In this study, the effect of both green and black tea on the changes of emulsification was examined by measuring the droplet size and the surface area. A model emulsion system containing olive oil, phosphatidylcholine (PC), and bile salt was developed to simulate small intestinal conditions. Initial changes in droplet size (from 1.4 to 52.8 microm and from 1.4 to 25.9 microm) of the emulsion were observed in the presence of 1.04 mg/mL and 0.10 mg/mL of total catechins prepared from green and black tea, respectively. Both teas caused similar changes on the emulsion properties; however, black tea was more effective than green tea. The underlying mechanisms of actions of tea polyphenols are discussed.


Assuntos
Emulsificantes/farmacologia , Emulsões/química , Flavonoides/farmacologia , Intestino Delgado/química , Fenóis/farmacologia , Óleos de Plantas/química , Chá/química , Cafeína/análise , Catequina/análise , Catequina/química , Fenômenos Químicos , Físico-Química , Azeite de Oliva , Polifenóis
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