Studies on the biotransformation of ketamine. II--Quantitative significance of the N-demethylation pathway in rats in vivo determined by a novel stable isotope technique.
In order to determine the fraction of an intravenous bolus dose of ketamine which is metabolized in vivo to the corresponding N-desmethyl compound, norketamine, a novel stable isotope technique was developed and applied to a study in rats. Co-injection of equimolar amounts of deuterium-labeled ketamine and unlabeled norketamine to four animals, followed by gas chromatographic/mass spectrometric analysis of both the administered compounds and deuterium-labeled norketamine in plasma, yielded pharmacokinetic data from which the fraction of the parent drug subjected to N-demethylation (fm) was calculated from AUC data to be 36.8 +/- 2.4%. It is concluded that this stable isotope co-administration technique represents a powerful approach to the determination of fm, in that the pharmacokinetics of the metabolite of interest, given as the preformed compound and generated in vivo, are determined simultaneously. This experimental design thus obviates the influence of time-dependent changes in metabolite clearance which may complicate the interpretation of studies performed using the classical cross-over design.
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.
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Leung
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Baillie
D000818:Animals; D001711:Biotransformation; D003640:Dealkylation; D003903:Deuterium; D007649:Ketamine / Q000031:analogs & derivatives / Q000378:metabolism*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
D007649:Ketamine; D003903:Deuterium; C033419:norketamine