Midazolam metabolism is carried out rapidly by hepatic and small intestine cytochrome P450 (CYP3A4) enzymes to active and inactive metabolites.
The principal metabolite of midazolam is 1-hydroxymidazolam, which has approximately half the activity of the parent compound.
This active midazolam metabolism is rapidly conjugated to 1-hydroxymidazolam glucuronide and is subsequently cleared by the kidneys.
This glucuronide metabolite has substantial pharmacologic activity when present in high concentrations, as may occur in critically ill patients with renal insufficiency who are receiving continuous intravenous infusions of midazolam over prolonged period of time.
In these patients the glucuronide compound may have synergistic sedative effects with the parent compound.
The other pharmacologically active midazolam metabolism like 4-hydroxymidazolam and 1, 4-dihydroxy midazolam, which are minor metabolites, are not present in detectable concentration in the plasma following IV administration of midazolam.
Less than 0.03% of the dose is excreted in the urine as intact midazolam, 45 to 81% of the dose is excreted in urine as the conjugates of the metabolites.
The drugs such as cimetidine, erythromycin, calcium channel blockers, anti-fungal drugs, that inhibit cytochrome P450 enzymes inhibits the midazolam metabolism resulting in unexpected CNS depression. Cytochrome P450 3A enzymes also influence the metabolism of fentanyl.