Abstract
Background and PurposeOseltamivir is the most widely prescribed anti-influenza medication. However, in rare instances, it has been reported to stimulate behavioural activities in adolescents. The goal of this study was to determine the molecular mechanism responsible for these behavioural activities.Experimental ApproachWe performed an in vitro assay of MAO-A, the enzyme responsible for neurotransmitter degradation, using either the active form – oseltamivir carboxylate (OC) or the inactive prodrug – oseltamivir ethyl ester (OEE). We also analysed the docking of MAO-A with OEE or OC in silico. Mouse behaviours after OEE or OC administration were monitored using automated video and computer analysis.Key ResultsOEE, but not OC, competitively and selectively inhibited human MAO-A. The estimated Ki value was comparable with the Km values of native substrates of MAO-A. Docking simulations in silico based on the tertiary structure of MAO-A suggested that OEE could fit into the inner pocket of the enzyme. Behavioural monitoring using automated video analysis further revealed that OEE, not OC, significantly enhanced spontaneous behavioural activities in mice, such as jumping, rearing, sniffing, turning and walking.Conclusions and ImplicationsOur multilevel analyses suggested OEE to be the cause of the side effects associated with oseltamivir and revealed the molecular mechanism underlying the stimulated behaviours induced by oseltamivir in some circumstances.
Highlights
Ameliorating the side effects of clinically administered drugs is an important aspect of human health, even if the side effects occur rarely
Oseltamivir is administered as an inactive prodrug in an ethyl ester form, which is converted in vivo to its active carboxylate form, as shown in Figure 1A–C (Abdel-Rahman et al, 2011)
These findings suggest that oseltamivir ethyl ester (OEE), but not oseltamivir carboxylate (OC), has the capacity to exert behavioural effects, and that the ethyl ester group of OEE is important for the inhibitory effects on MAO-A (Figure 1C, D)
Summary
Ameliorating the side effects of clinically administered drugs is an important aspect of human health, even if the side effects occur rarely. In rare instances reported mainly in Japan, individuals receiving oseltamivir, who were typically under the age of 20 years, showed adverse psychological and neuropsychiatrical effects (Maxwell, 2007; Jefferson et al, 2009; Kitching et al, 2009; Nakamura et al, 2010; L’Huillier et al, 2011), such as dyskinaesia and depressive episodes (Chung and Joung, 2010; Kadowaki et al, 2011) These effects have been compiled in documents published by the US Food and Drug Administration (FDA) (http://www.fda.gov/ Safety/MedWatch/SafetyInformation/SafetyAlertsforHuman MedicalProducts/ucm095044.htm, UCM134319.pdf and UCM303004.pdf: URLs of other FDA information are shown in the Supporting Information). Mouse behaviours after OEE or OC administration were monitored using automated video and computer analysis
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