alexa Comparative pharmacology in the rat of ketamine and its two principal metabolites, norketamine and (Z)-6-hydroxynorketamine.
Pharmaceutical Sciences

Pharmaceutical Sciences

Journal of Clinical & Experimental Pharmacology

Author(s): Leung LY, Baillie TA

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Abstract (Z)-6-Hydroxynorketamine (3), a secondary metabolite of the dissociative anesthetic agent ketamine (1), was synthesized, and its central nervous system (CNS) properties were compared to those of the parent drug and the primary metabolite, norketamine (2). Administration of compounds 1 and 2 to rats (40 mg/kg iv) produced general anesthesia and also led to marked increases in spontaneous locomotor activity during the postanesthetic recovery phase. These effects were of significantly longer duration with 1 than with 2. In contrast, the same dose of 3 produced neither general anesthesia nor CNS excitation, despite the fact that 3 entered brain tissue readily from the systemic circulation. It is concluded that the CNS effects of 1 are attenuated by metabolism to 2 and are abolished by subsequent hydroxylation to produce 3. Moreover, the results suggest that the desirable anesthetic properties of 1 and related arylcyclohexylamines may be inseparable from their ability to produce adverse postanesthetic emergence reactions.
This article was published in J Med Chem and referenced in Journal of Clinical & Experimental Pharmacology

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