RESUMO
ZD4054 is an oral specific endothelin-A receptor antagonist in development for the treatment of hormone-resistant prostate cancer. Both renal and metabolic processes contribute to its overall clearance. Two preclinical in vitro studies investigated the metabolism of ZD4054 using human liver microsomes, individual cytochrome P450 (CYP) isozymes, and flavin-containing monooxygenase isoforms. Two Phase I open-label crossover volunteer studies subsequently investigated in vivo drug interactions between ZD4054 and the CYP450 inducer rifampicin or CYP3A4 inhibitor itraconazole. The most abundant metabolite produced in in vitro incubations accounted for 12.8% of radioactivity after ZD4054 was incubated with CYP3A4. No significant flavin-containing monooxygenase metabolism of ZD4054 was observed. In the in vivo studies, rifampicin co-administration reduced the area under the concentration-time curve and maximum plasma concentration of ZD4054 by 68% and 29%, respectively, whilst co-administration with itraconazole was associated with an increase in ZD4054 area under the curve of approximately 28%. While co-administration of CYP450 inducers might be associated with reduced efficacy of ZD4054, dose reduction is unlikely to be required with concomitant administration of CYP3A4 inhibitors.
Assuntos
Antagonistas do Receptor de Endotelina A , Saúde , Itraconazol/farmacologia , Pirrolidinas/metabolismo , Rifampina/farmacologia , Adolescente , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Cromatografia Líquida de Alta Pressão , Sistema Enzimático do Citocromo P-450/metabolismo , Demografia , Avaliação Pré-Clínica de Medicamentos , Interações Medicamentosas , Feminino , Humanos , Itraconazol/administração & dosagem , Masculino , Pessoa de Meia-Idade , Oxigenases/metabolismo , Pirrolidinas/efeitos adversos , Pirrolidinas/química , Pirrolidinas/farmacocinética , Rifampina/administração & dosagemRESUMO
We present in this paper compelling evidence supporting the three-wave traveling-wave theory developed by Pierce fifty years ago. The transition in a Smith-Purcell free-electron laser from low, through moderate amplified spontaneous emission, to strong gain conditions was carefully controlled. Below threshold, the emitted far-infrared power exhibits oscillations with a cubic dependence on the electron beam current. Both characteristics are expected in a three-wave interaction yet, to date, have not been observed.