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1.
J Pharmacol Exp Ther ; 325(3): 935-46, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18310472

RESUMO

After oral treatment (once daily) for 4 weeks with the potent bradykinin B(1) receptor antagonist methyl 3-chloro-3'-fluoro-4'-{(1R)-1-[({1-[(trifluoroacetyl)amino]cyclopropyl}carbonyl)-amino]ethyl}-1,1'-biphenyl-2-carboxylate (MK-0686), rhesus monkeys (Macaca mulatta) exhibited significantly reduced systemic exposure of the compound in a dose-dependent manner, suggesting an occurrence of autoinduction of MK-0686 metabolism. This possibility is supported by two observations. 1) MK-0686 was primarily eliminated via biotransformation in rhesus monkeys, with oxidation on the chlorophenyl ring as one of the major metabolic pathways. This reaction led to appreciable formation of a dihydrodiol (M11) and a hydroxyl (M13) product in rhesus liver microsomes supplemented with NADPH. 2) The formation rate of these two metabolites determined in liver microsomes from MK-0686-treated groups was > or = 2-fold greater than the value for a control group. Studies with recombinant rhesus P450s and monoclonal antibodies against human P450 enzymes suggested that CYP2C75 played an important role in the formation of M11 and M13. The induction of this enzyme by MK-0686 was further confirmed by a concentration-dependent increase of its mRNA in rhesus hepatocytes, and, more convincingly, the enhanced CYP2C proteins and catalytic activities toward CYP2C75 probe substrates in liver microsomes from MK-0686-treated animals. Furthermore, a good correlation was observed between the rates of M11 and M13 formation and hydroxylase activities toward probe substrates determined in a panel of liver microsomal preparations from control and MK-0686-treated animals. Therefore, MK-0686, both a substrate and inducer for CYP2C75, caused autoinduction of its own metabolism in rhesus monkeys by increasing the expression of this enzyme.


Assuntos
Acetamidas/farmacocinética , Benzoatos/farmacocinética , Antagonistas de Receptor B1 da Bradicinina , Sistema Enzimático do Citocromo P-450/metabolismo , Acetamidas/sangue , Acetamidas/urina , Animais , Benzoatos/sangue , Benzoatos/urina , Bile/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Sistema Enzimático do Citocromo P-450/genética , Feminino , Hepatócitos/metabolismo , Humanos , Macaca mulatta , Masculino , Microssomos Hepáticos/metabolismo , Receptor de Pregnano X , Receptor B1 da Bradicinina/metabolismo , Receptores de Esteroides/metabolismo , Proteínas Recombinantes/metabolismo
2.
Drug Metab Dispos ; 34(8): 1367-75, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16698892

RESUMO

The pharmacokinetics and metabolism of 1-(4-((4-phenyl-5-trifluoromethyl-2-thienyl)methoxy)benzyl)azetidine-3-carboxylic acid (MRL-A), a selective agonist for the sphingosine-1-phosphate 1 (S1P1) receptor, were investigated in rats and dogs. In both species, more than 50% of the dose was excreted in bile. Specific to the rat, and observed in bile, were a taurine conjugate of MRL-A and a glucuronide conjugate of an azetidine lactam metabolite. In dogs, a smaller portion of the dose (54% of administered dose) was excreted intact in bile, and the major metabolites detected were an azetidine N-oxide of MRL-A and an acylglucuronide of an N-dealkylation product. This latter metabolite was also observed in rat bile. Stereoselective formation of the N-oxide isomer was observed in dogs, whereas the rat produced comparable amounts of both isomers. The formation of a unique glutathione adduct was observed in rat bile, which was proposed to occur via N-dealkylation, followed by reduction of the putative aldehyde product to form the alcohol, and dehydration of the alcohol to generate a reactive quinone methide intermediate. Incubation of a synthetic standard of this alcohol in rat microsomes fortified with reduced glutathione or rat hepatocytes resulted in formation of this unique glutathione adduct.


Assuntos
Azetidinas/farmacocinética , Glutationa/metabolismo , Receptores de Lisoesfingolipídeo/agonistas , Tiofenos/farmacocinética , Administração Oral , Animais , Azetidinas/administração & dosagem , Azetidinas/urina , Bile/química , Biotransformação , Cães , Fezes/química , Injeções Intravenosas , Mucosa Intestinal/metabolismo , Masculino , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie , Tiofenos/administração & dosagem , Tiofenos/urina
3.
Bioorg Med Chem Lett ; 16(6): 1692-5, 2006 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-16377185

RESUMO

The synthesis of the first high specific activity S-35-labeled hERG radioligand, [(35)S]MK-0499, for use in HTS assays of drug candidates for hERG interaction is described. The radioligand is prepared by [(35)S]sulfonylation of a high diastereomeric excess (de) aniline precursor prepared from unlabeled MK-0499.


Assuntos
Benzopiranos/química , Benzopiranos/farmacologia , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Piperidinas/química , Piperidinas/farmacologia , Bloqueadores dos Canais de Potássio/síntese química , Compostos Radiofarmacêuticos/síntese química , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Bloqueadores dos Canais de Potássio/farmacologia , Ensaio Radioligante , Compostos Radiofarmacêuticos/farmacologia , Radioisótopos de Enxofre/química
4.
Toxicol Appl Pharmacol ; 194(1): 10-23, 2004 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-14728975

RESUMO

As a class, hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors can potentially cause skeletal myopathy. One statin, cerivastatin, has recently been withdrawn from the market due to an unacceptably high incidence of rhabdomyolysis. The mechanism underlying statin-induced myopathy is unknown. This paper sought to investigate the relationship among statin-induced myopathy, mitochondrial function, and muscle ubiquinone levels. Rats were administered cerivastatin at 0.1, 0.5, and 1.0 (mg/kg)/day or dose vehicle (controls) by oral gavage for 15 days. Samples of type I-predominant skeletal muscle (soleus) and type II-predominant skeletal muscle [quadriceps and extensor digitorum longus (EDL)], and blood were collected on study days 5, 10, and 15 for morphological evaluation, clinical chemistry, mitochondrial function tests, and analysis of ubiquinone levels. No histological changes were observed in any of the animals on study days 5 or 10, but on study day 15, mid- and high-dose animals had necrosis and inflammation in type II skeletal muscle. Elevated creatine kinase (CK) levels in blood (a clinical marker of myopathy) correlated with the histopathological diagnosis of myopathy. Ultrastructural characterization of skeletal muscle revealed disruption of the sarcomere and altered mitochondria only in myofibers with degeneration, while adjacent myofibers were unaffected and had normal mitochondria. Thus, mitochondrial effects appeared not to precede myofiber degeneration. Mean coenzyme Q9 (CoQ9) levels in all dose groups were slightly decreased relative to controls in type II skeletal muscle, although the difference was not significantly different in most cases. Mitochondrial function in skeletal muscle was not affected by the changes in ubiquinone levels. The ubiquinone levels in high-dose-treated animals exhibiting myopathy were not significantly different from low-dose animals with no observable toxic effects. Furthermore, ubiquinone levels did not correlate with circulating CK levels in treated animals. The results of this study suggest that neither mitochondrial injury, nor a decrease in muscle ubiquinone levels, is the primary cause of skeletal myopathy in cerivastatin-dosed rats.


Assuntos
Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Doenças Musculares/metabolismo , Piridinas/toxicidade , Ubiquinona/metabolismo , Animais , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/patologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Doenças Musculares/induzido quimicamente , Doenças Musculares/patologia , Ratos , Ratos Sprague-Dawley , Ubiquinona/efeitos dos fármacos
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