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THE DEVELOPMENT OF TOLERANCE TO KETAMINE IN RATS AND THE SIGNIFICANCE OF HEPATIC METABOLISM
Author(s) -
LIVINGSTON A.,
WATERMAN A.E.
Publication year - 1978
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1978.tb08641.x
Subject(s) - metabolite , ketamine , metabolism , microsome , chemistry , in vitro , pharmacology , endocrinology , in vivo , medicine , biology , biochemistry , anesthesia , microbiology and biotechnology
1 A decrease in sleeping time in rats pretreated with ten daily doses of ketamine compared to controls is shown. 2 This decrease in sleeping time is associated with a more rapid decrease in circulating and brain levels of ketamine and its N‐demethylated metabolite and higher levels of the subsequent oxidation metabolite in the pretreated animals. 3 Metabolism of ketamine to its N‐demethylated metabolite by liver homogenates in vitro was more rapid when the livers were obtained from ketamine pretreated rats. 4 Microsomal preparations from rat liver were capable of metabolizing ketamine to its N‐demethylated metabolite and this metabolite to the subsequent oxidation metabolite in vitro . The V max and K m for the first reaction calculated from loss of substrate were 433 mol mg −1 protein h −1 and 0.133 m m respectively and 199 nmol mg −1 protein h −1 and 0.121 m m for the second reaction. 5 The results indicate that tolerance to ketamine in rats is associated with increased hepatic metabolism which can also be demonstrated in vitro in liver homogenates.