Autoinduction in drug metabolism is a known phenomenon observed when a drug induces the
enzymes responsible for its own metabolism. The potency, rate and extent of autoinduction following a given treatment paradigm may have therapeutic implications in clinic as well as for in vivo pharmacological assessments in animals.
RO4938581, an imidazo-triazolo-
benzodiazepine, is a novel GABAAα5 negative modulator recently pursued for the treatment of
cognitive dysfunctions. As circulating plasma levels of
RO4938581 were shown to decrease rapidly after repeated dosing in rats, with
CYP1A2 being involved in the metabolism of the compound, we examined the potential role of RO4938581-mediated autoinduction of
CYP1A2. Incubation of rat hepatocytes with
RO4938581 revealed potent
CYP1A2 induction with significant increase in enzymatic activity at concentrations of 0.1nM and
RO4938581 was shown to be 700-fold more potent than β-napththoflavone. Ex vivo studies revealed a 7-fold increase in metabolic
CYP1A2 activity in liver microsomes prepared from rats administered with 0.1mg/kg of
RO4938581 24h before. This induction profile was reflected in vivo in pharmacokinetic studies in rats where an 8-fold reduction in plasma exposure was observed after a second dose. The reduction in plasma exposures due to
CYP1A2 autoinduction were confirmed functionally in contextual fear conditioning paradigm in rats, where a positive pharmacological effect observed after acute drug administration disappeared completely after sub-chronic dosing. Together, these findings suggest that
RO4938581 possesses potent
CYP1A2 autoinductive properties in rats and may serve as a tool for mechanistic metabolism or drug-drug interaction studies encircling this
enzyme in rats.