Midazolam has been shown to be a mechanism-based inhibitor in vitro. However, available data does not indicate that it is an inhibitor or an inducer of CYP enzymes in vivo.

Cyclic tertiary amide functions, such as present in the imidazole grouping, are associated with CYP suicide properties.

Midazolam injection is a short-acting sleep-inducing drug which is indicated for conscious sedation, anaesthesia and sedation in intensive care units. Midazolam oromucosal solution is indicated for the treatment of prolonged, acute, convulsive seizures in infants, toddlers, children and adolescents (from 3 months to <18 years). Less common side effects are nausea, vomiting and obstipation.

Midazolam is metabolised by CYP3A4 and the main metabolite is alfa-hydroxymidazolam. Alfa-hydroxymidazolam is pharmacologically active, but contributes minimally (about 10%) to the effects of intravenous midazolam (SPC). In healthy volunteers the half-life elimination of midazolam is 1.5-2.5 hours. Midazolam is not listed as an inhibitor or an inducer of CYP3A4 or any other major CYP enzymes in vivo (FDA, Hisaka 2010 and Pelkonen 2008). In vitro this drug has been shown to cause time-dependent inhibition of CYP3A4 (Bomsien 2006 and Podoll 1996), other human CYP450 enzymes (Grimm 2009) and that the 1-hydroxylation of midazolam takes place under destruction of CYP3A (Khan 2002 and Masubuchi 2007). However, no drug-drug interactions with midazolam as a perpetrator have been observed (Interaksjoner and Interaktionsdatabsen), which indicates that midazolam is not an inhibitor or inducer of CYP enzymes in vivo.

Thunell: 3 reports of safe use. Reports of repeated use in children without porphyric side effects.

Midazolam is listed as safe in acute porphyria (Gorchein 1997) and has not been associated with human porphyric attacks (Moore 1997). In a review focusing on drugs and the anaesthetic implication in acute porphyrias (James 2000) midazolam is listed in the category Use with caution with the following description: Though safety is not established beyond doubt, the evidence suggests that the drug is unlikely to prove unsafe in practice. It may be used provided no safer alternative is available or suitable. In a case report (Armen 2009) a female AIP patient was given several drugs including midazolam during surgery without triggering an acute attack. The authors conclude that midazolam is safe for use in patients with acute porphyria. The patient was however, also given heme and glucose to inhibit heme synthesis and prevent an acute attack which means that a possible acute attack could have been supressed. In another report midazolam was used uneventfully in a 60 year old, menopausal, AIP patient (Hsieh 2006).

Uneventful use reported in 2 patients with acute porphyria.