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1.
J Pharmacol Exp Ther ; 330(3): 911-21, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19502531

RESUMO

Baclofen is a racemic GABA(B) receptor agonist that has a number of significant pharmacokinetic limitations, including a narrow window of absorption in the upper small intestine and rapid clearance from the blood. Arbaclofen placarbil is a novel transported prodrug of the pharmacologically active R-isomer of baclofen designed to be absorbed throughout the intestine by both passive and active mechanisms via the monocarboxylate type 1 transporter. Arbaclofen placarbil is rapidly converted to R-baclofen in human and animal tissues in vitro. This conversion seems to be primarily catalyzed in human tissues by human carboxylesterase-2, a major carboxylesterase expressed at high levels in various tissues including human intestinal cells. Arbaclofen placarbil was efficiently absorbed and rapidly converted to R-baclofen after oral dosing in rats, dogs, and monkeys. Exposure to R-baclofen was proportional to arbaclofen placarbil dose, whereas exposure to intact prodrug was low. Arbaclofen placarbil demonstrated enhanced colonic absorption, i.e., 5-fold higher R-baclofen exposure in rats and 12-fold higher in monkeys compared with intracolonic administration of R-baclofen. Sustained release formulations of arbaclofen placarbil demonstrated sustained R-baclofen exposure in dogs with bioavailability up to 68%. In clinical use, arbaclofen placarbil may improve the treatment of patients with gastroesophageal reflux disease, spasticity, and numerous other conditions by prolonging exposure and decreasing the fluctuations in plasma levels of R-baclofen.


Assuntos
Baclofeno/farmacocinética , Agonistas GABAérgicos/farmacocinética , Pró-Fármacos/farmacocinética , Animais , Ligação Competitiva/efeitos dos fármacos , Butiratos/metabolismo , Carboxilesterase/metabolismo , Hidrolases de Éster Carboxílico/metabolismo , Células Cultivadas , Química Farmacêutica , Sistema Enzimático do Citocromo P-450/metabolismo , Humanos , Hidrólise , Absorção Intestinal , Isobutiratos , Isoenzimas/efeitos dos fármacos , Células LLC-PK1 , Masculino , Membranas Artificiais , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual , Vinho
3.
Bioorg Med Chem ; 11(4): 591-600, 2003 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-12538024

RESUMO

SAR studies in a series of related 3-(heteroarylthio)cephems determined that a relatively high chemical reactivity of the beta-lactam ring, modulated by electronic effects of substituents at C-3 and C-7, is necessary to achieve high in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA). Such high reactivity results in lowered hydrolytic stability and concomitantly increases susceptibility to beta-lactam ring opening mediated by serum enzymes. Therefore, optimization of anti-MRSA activity versus stability toward serum-mediated degradation required a fine balance of substituent effects. Serum stability studies (measured as percentage of parent drug degraded after 60 min incubation) revealed up to 80-fold difference in degradation rate in a series of closely related (3-heteroarylthio)cephems. Of the compounds evaluated, RWJ-333441 (MC-04,546) possessed the best balance of serum stability (6% degradation after 60 min incubation) and in vitro activity versus MRSA (S. aureus COL MIC=1 microgram/mL). Accordingly, RWJ-333441 displayed excellent in vivo efficacy versus methicillin-susceptible Staphylococcus aureus (MSSA, ED(50)=0.39 mg/kg in mouse sepsis model with S. aureus Smith) and good pharmacokinetic properties in the rat (Cl(total)=0.39 L/h/kg).


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Cefalosporinas/química , Cefalosporinas/farmacologia , Lactamas , Animais , Antibacterianos/farmacocinética , Cefalosporinas/farmacocinética , Desenho de Fármacos , Humanos , Indicadores e Reagentes , Masculino , Resistência a Meticilina , Camundongos , Testes de Sensibilidade Microbiana , Ratos , Ratos Sprague-Dawley , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade
4.
Bioorg Med Chem Lett ; 14(20): 5133-7, 2004 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-15380214
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