Identification of the Cytochrome P450 and Other Enzymes Involved in the In Vitro Oxidative Metabolism of a Novel Antidepressant, Lu AA21004
- 11 April 2012
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Drug Metabolism and Disposition
- Vol. 40 (7), 1357-1365
- https://doi.org/10.1124/dmd.112.044610
Abstract
1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine (Lu AA21004) is a novel antidepressant that is currently in late-stage clinical development for major depressive disorder. In the present study, the metabolism of Lu AA21004 was investigated using human liver microsomes (HLM), human liver S9 fraction, and recombinant enzymes. Lu AA21004 was found in vitro to be oxidized to a 4-hydroxy-phenyl metabolite, a sulfoxide, an N-hydroxylated piperazine, and a benzylic alcohol, which was further oxidized to the corresponding benzoic acid [3-methyl-4-(2-piperazin-1-yl-phenysulfanyl)-benzoic acid (Lu AA34443)]. The formation of the 4-hydroxy-phenyl metabolite was catalyzed by CYP2D6 with some contribution from CYP2C9, whereas the formation of the sulfoxide was mediated by CYP3A4/5 and CYP2A6. CYP2C9 and CYP2C19 were the primary enzymes responsible for formation of the N-hydroxylated metabolite. The benzylic alcohol was formed by CYP2D6 only. The oxidation of the benzylic alcohol to the corresponding benzoic acid of Lu AA21004 was catalyzed by alcohol dehydrogenase and aldehyde dehydrogenase, with some contribution from aldehyde oxidase. CYP2D6 was also capable of catalyzing the formation of the benzoic acid of Lu AA21004; however, its overall contribution to this pathway was negligible. Enzyme kinetic parameters revealed that the rate-limiting step in the formation of the benzoic acid from Lu AA21004 is the formation of the corresponding alcohol. Thus, the intrinsic clearance (Vmax/Km) in HLM for metabolism of Lu AA21004 to the benzylic alcohol was 1.13 × 10−6 l · min−1 · mg−1, whereas the subsequent metabolism of the benzylic alcohol to the benzoic acid of Lu AA21004 is characterized by an intrinsic clearance (Vmax/Km) in S9 fraction of 922 × 10−6 l · min−1 · mg−1.Keywords
This publication has 14 references indexed in Scilit:
- Biosynthesis and Identification of an N-Oxide/N-Glucuronide Metabolite and First Synthesis of an N-O-Glucuronide Metabolite of Lu AA21004Drug Metabolism and Disposition, 2011
- Discovery of 1-[2-(2,4-Dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): A Novel Multimodal Compound for the Treatment of Major Depressive DisorderJournal of Medicinal Chemistry, 2011
- P.2.c.040 A randomised, double-blind, placebo-controlled, active-referenced study of Lu AA21004 in patients with major depressionEuropean Neuropsychopharmacology, 2009
- POTENT INHIBITION OF HUMAN LIVER ALDEHYDE OXIDASE BY RALOXIFENEDrug Metabolism and Disposition, 2004
- THE CONDUCT OF IN VITRO AND IN VIVO DRUG-DRUG INTERACTION STUDIES: A PHARMACEUTICAL RESEARCH AND MANUFACTURERS OF AMERICA (PhRMA) PERSPECTIVEDrug Metabolism and Disposition, 2003
- An Extremely Potent Inhibitor of Xanthine OxidoreductaseJournal of Biological Chemistry, 2003
- Human Drug Metabolism and the Cytochromes P450: Application and Relevance of In Vitro ModelsThe Journal of Clinical Pharmacology, 2001
- Optimising drug development: strategies to assess drug metabolism/transporter interaction potential — towards a consensusEuropean Journal of Pharmaceutical Sciences, 2001
- Inhibition of Recombinant Human Mitochondrial and Cytosolic Aldehyde Dehydrogenases by Two Candidates for the Active Metabolites of DisulfiramBiochemistry, 1997
- Possible Role of Liver Cytosolic and Mitochondrial Aldehyde Dehydrogenases in Acetaldehyde MetabolismBiochemistry, 1996