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Vol. 28, Issue 6, 633-642, June 2000

Metabolism of A Dopamine D4-Selective Antagonist in Rat, Monkey, and Humans: Formation of A Novel Mercapturic Acid Adduct

Kanyin E. Zhang,1 Prasad H. Kari, Margaret R. Davis,2 George Doss, Thomas A. Baillie, and Kamlesh P. Vyas

Department of Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania and Rahway, New Jersey

3-{[4-(4-Chlorophenyl)piperazin-1-yl]-methyl}-1H-pyrrolo-2,3-beta -pyridine (L-745,870) is a dopamine D4 selective antagonist that has been studied as a potential treatment for schizophrenia, with the expectation that it would not exhibit the extrapyramidal side effects often observed with the use of classical antipsychotic agents. The metabolism of L-745,870 in vivo was investigated in the rat, rhesus monkey, and human using liquid chromatography-tandem mass spectrometry and/or NMR techniques in conjunction with radiochemical detection. In all three species, two major metabolic pathways were identified, namely N-dealkylation at the substituted piperazine moiety and the formation of a novel mercapturic acid adduct. It is proposed that the latter biotransformation process involves the formation of an electrophilic imine methide intermediate, analogous to that produced from 3-methyl indole. This report appears to represent the first example of metabolic activation of a 3-alkyl-7-azaindole nucleus.

1 Current address: Department of Development Pharmacology, Agouron Pharmaceuticals, Inc., San Diego, CA.

2 Current address: Cerep, Inc., 15318 NE 95th St., Redmond, WA.

Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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