RESUMO
Monkeys have been proposed as an animal model to predict the magnitude of human clinical drug-drug interactions caused by CYP3A4 enzyme induction. To evaluate whether the cynomolgus monkey can be an effective in vivo model, human CYP3A4 inducers were evaluated both in vitro and in vivo. First, a full-length pregnane X receptor (PXR) was cloned from the cynomolgus monkey, and the sequence was compared with those of rhesus monkey and human PXR. Cynomolgus and rhesus monkey PXR differed by only one amino acid (A68V), and both were highly homologous to human PXR (approximately 96%). When the transactivation profiles of 30 compounds, including known inducers of CYP3A4, were compared between cynomolgus and human PXR, a high degree of correlation with EC(50) values was observed. These results suggest that cynomolgus and human PXR respond in a similar fashion to these ligands. Second, two known human CYP3A4 inducers, rifampicin and hyperforin, were tested in monkey and human primary hepatocytes for induction of CYP3A enzymes. Both monkey and human hepatocytes responded similarly to the inducers and resulted in increased RNA and enzyme activity changes of CYP3A8 and CYP3A4, respectively. Lastly, in vivo induction of CYP3A8 by rifampicin and hyperforin was shown by significant reductions of midazolam exposure that were comparable with those in humans. These results show that the cynomolgus monkey can be a predictive in vivo animal model of PXR-mediated induction of human CYP3A4 and can provide a useful assessment of the resulting pharmacokinetic changes of affected drugs.
Assuntos
Citocromo P-450 CYP3A/biossíntese , Hepatócitos/metabolismo , Macaca fascicularis , Receptores de Esteroides/metabolismo , Xenobióticos/farmacocinética , Adulto , Sequência de Aminoácidos , Animais , Compostos Bicíclicos com Pontes/sangue , Compostos Bicíclicos com Pontes/farmacocinética , Compostos Bicíclicos com Pontes/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Clonagem Molecular , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Interações Medicamentosas/genética , Indução Enzimática/efeitos dos fármacos , Indução Enzimática/genética , Feminino , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Humanos , Hypericum/química , Macaca mulatta , Masculino , Midazolam/sangue , Midazolam/metabolismo , Midazolam/farmacocinética , Pessoa de Meia-Idade , Modelos Animais , Dados de Sequência Molecular , Floroglucinol/análogos & derivados , Floroglucinol/sangue , Floroglucinol/farmacocinética , Floroglucinol/farmacologia , Extratos Vegetais/sangue , Extratos Vegetais/farmacocinética , Receptor de Pregnano X , Receptores de Esteroides/genética , Rifampina/sangue , Rifampina/farmacocinética , Rifampina/farmacologia , Homologia de Sequência de Aminoácidos , Terpenos/sangue , Terpenos/farmacocinética , Terpenos/farmacologia , Ativação Transcricional/efeitos dos fármacos , Ativação Transcricional/genética , TransfecçãoRESUMO
The SXR humanized mouse model was used to quantitatively assess an in vivo induction response of the human PXR agonist, rifampicin. Three days of rifampicin treatment increased RNA expression and microsomal enzyme activity of CYP3A11, as well as significantly reduced triazolam plasma exposure. These results indicate that the humanized SXR mouse can be used as a model to predict human CYP3A4 induction and the resulting pharmacokinetic changes of CYP3A4 substrates in humans.
Assuntos
Citocromo P-450 CYP3A/efeitos dos fármacos , Proteínas de Membrana/efeitos dos fármacos , Receptores de Esteroides/agonistas , Rifampina/farmacologia , Animais , Antibióticos Antituberculose/administração & dosagem , Antibióticos Antituberculose/farmacologia , Citocromo P-450 CYP3A/metabolismo , Relação Dose-Resposta a Droga , Interações Medicamentosas , Indução Enzimática/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Modelos Animais , Receptor de Pregnano X , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Rifampina/administração & dosagem , Especificidade da Espécie , Triazolam/farmacocinéticaRESUMO
The synthesis and antifungal activity of 5'- and 5'-6'-substituted azasordarin derivatives are described. Modification of the 5'-position led to the discovery of the spirocyclopentyl analogue 7g, which is the first azasordarin to register single-digit MIC values versus Aspergillus spp. Further investigation identified the 5'-i-Pr derivative 7b, which displays superior pharmacokinetic properties compared to other azasordarins.