Biotransformation of 3-Amino-5,6,7,8-tetrahydro-2-{4-[4-(quinolin-2-yl)piperazin-1-yl]butyl}quinazolin-4(3H)-one (TZB-30878), a Novel 5-Hydroxytryptamine (5-HT)_1A Agonist/5-HT₃ Antagonist, in Human Hepatic Cytochrome P450 Enzymes

Abstract

Irritable bowel syndrome (IBS) is a common multifactorial disorder with a largely undefined etiology. Symptoms of IBS, such as abdominal pain and diarrhea, commonly develop and persist in patients who are in remission from other stress-related diseases. To develop a medication for patients with IBS, we focused on the properties of 5-hydroxytryptamine (5-HT) 1A agonism and 5-HT 3 antagonism and synthesized a novel compound, TZB-30878 (Fig. 1). This compound was expected to have anxiolytic action via 5-HT 1A agonism and to suppress intestinal motility and visceral hypersensitivity via 5-HT 3 antagonism. TZB-30878 was previously shown to exhibit potent and highly selective serotonin 5-HT 3 receptor antagonistic activities and also a high affinity for the 5-HT 1A receptor subtype that contributes to an overall therapeutic effect (Tamaoki et al., 2007). The pharmacokinetics and excretion of TZB-30878 have been studied in vivo in rats previously (unpublished data). The results indicated that TZB-30878 is rapidly absorbed following p.o. administration, distributed to almost all the organs including brain, and eliminated into feces via bile. However, there is very limited information regarding metabolism of TZB-30878.The objective of this study was to clarify the biotransformation of TZB-30878 in humans. We characterized the chemical structures of metabolites and identified the human hepatic cytochromes P450 (P450) responsible for the metabolism of TZB-30878. Materials and MethodsChemicals. Trifluoroacetic acid, Tris, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, and ammonium acetate were purchased from Nacalai Tesque Inc. (Kyoto, Japan). ␣-Naphthoflavone, sulfaphenazole, quinidine hydrochloride, and diethyldithiocarbamic acid sodium salt (diethyldithiocarbamate) were purchased from Sigma-Aldrich (St. Louis, MO). ␤-NADP ϩ ,Article, publication date, and citation information can be found at http://dmd.aspetjournals.org. doi:10.1124/dmd.107.018168.ABBREVIATIONS: IBS, irritable bowel syndrome; 5-HT, 5-hydroxytryptamine; 6,7,