Metabolism—Midazolam

Midazolam is a 3A4 substrate in human, and has been used as a probe for examining 3A variants in man.  Using midazolam as a probe in humanized animals is challenging because humans and rodents produce the same metabolites and in relatively similar proportions – the 1’OH metabolite is predominant.  In this experiment we simply set out to discover and understand if we could at least distinguish between the two species in a relative sense.

Even though both 1’OH and 4-OH metabolites are formed in both species, there is a clear difference between the two systems which makes it possible to conduct drug-drug interaction studies in the systems even though identical metabolites are present.  Interestingly, we did not observe a significant difference in clearance rates of midazolam between humanized and control animals.