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1.
Drug Metab Dispos ; 41(4): 916-22, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23388705

RESUMO

The high density of A1 adenosine receptors in the brain results in significant potential for central nervous system (CNS)-related adverse effects with A1 agonists. Tecadenoson is a selective A1 adenosine receptor agonist with close similarity to adenosine. We studied the binding and transmembrane transport of tecadenoson by recombinant human equilibrative nucleoside transporters (hENTs) hENT1 and hENT2, and human concentrative nucleoside transporters (hCNTs) hCNT1, hCNT2, and hCNT3 in vitro and by mouse mENT1 in vivo. Binding affinities of the five recombinant human nucleoside transporters for tecadenoson differed (hENT1 > hCNT1 > hCNT3 > hENT2 > hCNT2), and tecadenoson was transported largely by hENT1. Pretreatment of mice with a phosphorylated prodrug of nitrobenzylmercaptopurine riboside, an inhibitor of mENT1, significantly decreased brain exposure to tecadenoson compared with that of the untreated (control) group, suggesting involvement of mENT1 in transport of tecadenoson across the blood-brain barrier (BBB). In summary, ENT1 was shown to mediate the transport of tecadenoson in vitro with recombinant and native human protein and in vivo with mice. The micromolar apparent Km value of tecadenoson for transport by native hENT1 in cultured cells suggests that hENT1 will not be saturated at clinically relevant (i.e., nanomolar) concentrations of tecadenoson, and that hENT1-mediated passage across the BBB may contribute to the adverse CNS effects observed in clinical trials. In contrast, in cases in which a CNS effect is desired, the present results illustrate that synthetic A1 agonists that are transported by hENT1 could be used to target CNS disorders because of enhanced delivery to the brain.


Assuntos
Agonistas do Receptor A1 de Adenosina/farmacocinética , Adenosina/análogos & derivados , Barreira Hematoencefálica/metabolismo , Transportador Equilibrativo 1 de Nucleosídeo/metabolismo , Furanos/farmacocinética , Proteínas de Transporte de Nucleosídeos/metabolismo , Pró-Fármacos/farmacologia , Tioinosina/análogos & derivados , Adenosina/farmacocinética , Marcadores de Afinidade/farmacologia , Animais , Transporte Biológico/efeitos dos fármacos , Encéfalo/metabolismo , Células Cultivadas , Transportador Equilibrativo 1 de Nucleosídeo/antagonistas & inibidores , Humanos , Moduladores de Transporte de Membrana/farmacologia , Camundongos , Tioinosina/farmacologia
2.
J Pharm Biomed Anal ; 37(2): 351-8, 2005 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-15708677

RESUMO

The compound, 5-{4-[3-(4-cyclohexyl-2-propylphenoxy)propoxy]phenyl}-1,3-oxazolidine-2,4-dione (compound A) is a peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist. PPARgamma agonists have proven useful in the treatment of type 2 diabetes, which is characterized by hyperglycemia, insulin resistance and/or abnormal insulin secretion. The metabolism of this oxazolidinedione (OZD) was investigated in male rat, dog, monkey and human liver microsomes, and recombinant human cytochrome P450 enzymes (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4) in the presence of NADPH. Routes of metabolism included monohydroxylation of the cyclohexane ring at multiple positions, monohydroxylation of the n-propyl side chain or the tether linkage, and OZD ring opening, giving rise to the keto amide and alcohol amide entities. Liver microsomes showed subtle qualitative and quantitative metabolic differences among rat, dog, monkey and human preparations. Further, CYP2C8 and CYP2C19 did not display different regioselectivity for hydroxylation on the cyclohexane ring with both of them giving rise to C-3 and C-4 hydroxy metabolites, but they did display different stereoselectivity with CYP2C8 preferring cyclohexane hydroxylation in equatorial positions and CYP2C19 in axial positions.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Hipoglicemiantes/metabolismo , Microssomos Hepáticos/metabolismo , Oxazóis/metabolismo , Oxazolidinonas/metabolismo , PPAR alfa/agonistas , Proteínas Recombinantes/metabolismo , Animais , Cromatografia Líquida , Cães , Humanos , Hidroxilação , Espectroscopia de Ressonância Magnética , Masculino , Espectrometria de Massas , Ratos
3.
Pharm Res ; 21(6): 996-9, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15212165

RESUMO

PURPOSE: To investigate the in vitro trans-esterification of 1-[2(R)-(2-amino-2-methylpropionylamino)-3-(1H-indol-3-yl)propionyl]-3(S)-benzyl-piperidine-3-carboxylic acid ethyl ester (compound A) and to determine the effects of ethanol on its in vivo pharmacokinetics in male Sprague-Dawley rats. METHODS: The effects of deuterated [d5]ethanol on the hydrolysis and trans-esterification of compound A in rat plasma and rat liver microsomes in the presence or absence of bis(p-nitrophenyl) phosphate (BNPP), a carboxylesterase inhibitor, were investigated. Following an oral pretreatment with deuterated ethanol in conjunction with an intravenous dose of compound A to rats, the pharmacokinetics of compound A and deuterated compound A were evaluated. RESULTS: It was observed that the amount of deuterated compound A generated increased with increasing amounts of deuterated ethanol in incubates, whereas the amount of hydrolyzed product (compound B) decreased. BNPP inhibited both the hydrolysis and the trans-esterification of compound A. Furthermore, the pharmacokinetics of compound A in rats receiving ethanol was altered, such that the plasma clearance decreased by 1.5-fold and the elimination rate constant decreased by 2-fold. Deuterated compound A was determined, confirming that trans-esterification proceeded in vivo; approximately one third of the intravenous dose of compound A underwent trans-esterification. CONCLUSIONS: In the presence of ethanol, compound A underwent trans-esterification catalyzed by carboxylesterases. Ethanol pretreatment resulted in a decrease in the in vivo clearance of compound A mainly due to trans-esterification with ethanol.


Assuntos
Ácidos Carboxílicos/metabolismo , Esterificação/efeitos dos fármacos , Ésteres/metabolismo , Ésteres/farmacocinética , Etanol/farmacocinética , Piperidinas/metabolismo , Piperidinas/farmacocinética , Administração Oral , Animais , Área Sob a Curva , Ácidos Carboxílicos/administração & dosagem , Ácidos Carboxílicos/farmacocinética , Hidrolases de Éster Carboxílico/metabolismo , Cromatografia Líquida/métodos , Deutério , Avaliação Pré-Clínica de Medicamentos/métodos , Interações Medicamentosas/fisiologia , Ésteres/administração & dosagem , Etanol/administração & dosagem , Etanol/sangue , Hormônio do Crescimento Humano/efeitos dos fármacos , Hormônio do Crescimento Humano/metabolismo , Hidrólise/efeitos dos fármacos , Injeções Intravenosas , Masculino , Espectrometria de Massas/métodos , Taxa de Depuração Metabólica/efeitos dos fármacos , Taxa de Depuração Metabólica/fisiologia , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Nitrofenóis/farmacologia , Piperidinas/administração & dosagem , Ratos , Ratos Sprague-Dawley
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