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Pharmacokinetics of a novelN-methyl-D-aspartate receptor antagonist (SM-18400): Identification of anN-acetylated metabolite and pre-clinical assessment ofN-acetylation polymorphism

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Summary

(S)-9-chloro-5-[p-aminomethyl-o-(carboxymethoxy)phenylcarbamoylmethyl]-6,7-dihydro-1H,5H-pyrido[1,2,3-de]quinoxaline-2,3-dion hydrochloride trihydrate (SM-18400) was given intravenously to rats and dogs and its pharmacokinetics was investigated. By LC/MS/MS analysis, the major metabolite in the rat serum was identified asN-acetylated SM-18400 (SM-NAc). In rats,AUC ratio of SM-NAc to SM-18400 was approximately 50%. However, 71% of the dose was excreted as unchanged SM-18400 and only 9.8% as SM-NAc in the urine and bile, indicating that the contribution ofN-acetylation clearance (CLNAc) to the total clearance (CLtot) is limited to 10–30% in rats. No SM-NAc or other metabolites were detected in the dog serum, urine or bile. Thein vitro intrinsic clearance (CLint, ml/min/mg cytosolic protein) ofN-acetyltransferase (NAT) activities of dog liver cytosol towards SM-18400 and hepaticN-acetylation clearance (CLNAc, ml/min/kg body weight) estimated by well-stirred model were both only 5% of the respective rat value, well reflecting the relativein vivo CLNAc/CLtot ratios.CLint values for human live cytosol samples (n=4) and estimatedCLNAc were all less than 18% and 7% of the rat, respectively. Based on these results, we concluded that theCLNAc/CLtot of human would be small enough to avoid major inter-individual variance in SM-18400 pharmacokinetics due toN-acetylation polymorphism. In addition, even a human liver cytosol sample lacking polymorphic NAT2 activity as determined by sulfamethazine (SMZ)N-acetylation analysis, proved capable of acetylating SM-18400, suggesting that NAT2 is not the major enzyme responsible forN-acetylation of SM-18400 in human. This fact would also reduce the risk ofN-acetylation polymorphism playing a role in clinical use of this drug.

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Abbreviations

SM-18400:

(S)-9-chloro-5-[p-aminomethyl-o-(carboxymethoxy)phenylcarbanoylmethyl]-6,7-dihydro-1H,5H-pyrido[1,2,3-de]quinoxaline-2,3-dion hydrochloride trihydrate

NMDA:

N-methyl-D-aspartate

CL NAc :

N-acetylation clearance

SM-NAc:

N-acetylated SM-18400

P ABA:

p-aminobenzoic acid

SMZ:

sulfamethazine

DTT:

dithiothreitol

AcCoA:

acetyl coenzyme A

[14C]SM-18400:

[quinoxaline-2,3-14C]SM-18400

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Authors and Affiliations

  1. Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd, 3-1-98, Kasugade-naka, Konohana-ku, 554-8558, Osaka, Japan

    Masashi Yabuki Ph. D., Yutaka Kon-Ya, Masaki Kataoka, Takeshi Shimizudani, Kyoko Akao, Masaki Ito, Hiroshi Kanamaru & Iwao Nakatsuka

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  1. Masashi Yabuki Ph. D.
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  2. Yutaka Kon-Ya
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Yabuki, M., Kon-Ya, Y., Kataoka, M. et al. Pharmacokinetics of a novelN-methyl-D-aspartate receptor antagonist (SM-18400): Identification of anN-acetylated metabolite and pre-clinical assessment ofN-acetylation polymorphism. Eur. J. Drug Metab. Pharmacokinet. 28, 21–29 (2003). https://doi.org/10.1007/BF03190863

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