Evidence of CYP3A Allosterism In Vivo: Analysis of Interaction Between Fluconazole and Midazolam

The allosteric effect of fluconazole (effector) on the formation of 1’-hydroxymidazolam (1’-OH-MDZ) and 4-hydroxymidazolam (4-OH-MDZ) from the CYP3A4/5 substrate, midazolam (MDZ), was examined in healthy volunteers. Following pre-treatment of fluconazole, AUC(4-OH)/AUC(MDZ) increased 35–62%, while AUC(1’-OH)/AUC(MDZ) decreased 5–37%; AUC(1’-OH)/AUC(4-OH) ratio decreased 46–58% by fluconazole and had no association with CYP3A5 genotype. 1’-OH-MDZ formation in vitro was more susceptible than 4-OH-MDZ formation to inhibition by fluconazole. Fluconazole decreased the intrinsic formation clearance ratio of 1’-OH-MDZ/4-OH-MDZ to an extent that was quantitatively comparable to in vivo observations. The elimination clearance of midazolam metabolites appeared unaffected by fluconazole. This study demonstrated that fluconazole alters midazolam product formation both in vivo and in vitro in a manner consistent with an allosteric interaction. The 1'-OH-MDZ/4-OH-MDZ ratio may serve as a biomarker of such interactions between midazolam, CYP3A4/5 and other putative effectors

Valuing the voices of young disabled People: Exploring experience of physical education and sport

This article will report on the process of student-led research as an innovative pedagogical technique for learning more about the physical education (PE) and sporting experiences of young disabled people. The article draws on work from two school based curriculum projects that sought to work with young people in an empowering manner. We argue that student-led project work can place value on students voices, promote dialogue between students and teachers and enables students' to enhance their awareness and reflective capacity.We propose that as researchers we need to rethink our understanding of the research process if we are to support research centralising the voices of young people