PT - JOURNAL ARTICLE AU - Kouichi Minato AU - Ryota Suzuki AU - Akira Asagarasu AU - Teruaki Matsui AU - Michitaka Sato TI - Biotransformation of 3-Amino-5,6,7,8-tetrahydro-2-{4-[4-(quinolin-2-yl)piperazin-1-yl]butyl}quinazolin-4(3<em>H</em>)-one (TZB-30878), a Novel 5-Hydroxytryptamine (5-HT)<sub>1A</sub> Agonist/5-HT<sub>3</sub> Antagonist, in Human Hepatic Cytochrome P450 Enzymes AID - 10.1124/dmd.107.018168 DP - 2008 May 01 TA - Drug Metabolism and Disposition PG - 831--840 VI - 36 IP - 5 4099 - http://dmd.aspetjournals.org/content/36/5/831.short 4100 - http://dmd.aspetjournals.org/content/36/5/831.full SO - Drug Metab Dispos2008 May 01; 36 AB - 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, is currently under development for the treatment of irritable bowel syndrome. The objective of this investigation was to obtain information on the biotransformation of TZB-30878. This compound has quinazoline, piperazine, and quinoline rings. Metabolites of [quinazoline-2-14C]TZB-30878 were determined using radio high-performance liquid chromatography on samples obtained after incubation with human hepatic microsomes. Eight metabolites were detected in the microsomal incubation mixture, and their structures were proposed by mass spectrometry techniques using TZB-30878 and two stable labeled TZB-30878 analogs, [quinoline-deuterium (D)6]TZB-30878 and [piperazin-D8]TZB-30878. Liquid chromatography/tandem mass spectrometry analyses suggested that the eight metabolites consisted of a cyclic metabolite (M6), four hydroxylated metabolites (M1, M2, M3, and M4) (three on quinoline ring and one on quinazoline ring), a deaminated metabolite (M5), and two metabolites (M7 and M8) that were presumably intermediates leading to the formation of the cyclic metabolite M6. Hydroxylation sites in the quinoline and quinazoline rings were predicted by electron density calculations and confirmed by comparison with authentic standards. To the best of our knowledge, N-deamination by microsomes leading to the formation of M5 appears to be novel. In addition, in vitro experiments in human liver microsomes with cytochrome P450 (P450)-specific inhibitors revealed that CYP3A4 was the major enzyme responsible for the metabolism of TZB-30878. Other P450 enzymes, such as a CYP2D6, played a minor role in its metabolism. The American Society for Pharmacology and Experimental Therapeutics