Oxidative metabolism of 5-methoxy- N, N-diisopropyltryptamine (Foxy) by human liver microsomes and recombinant cytochrome P450 enzymes

• Published in: Biochemical pharmacology Vol. 71; no. 9; pp. 1377 - 1385
• Main Authors: Narimatsu, Shizuo, Yonemoto, Rei, Saito, Keita, Takaya, Kazuo, Kumamoto, Takuya, Ishikawa, Tsutomu, Asanuma, Masato, Funada, Masahiko, Kiryu, Kimio, Naito, Shinsaku, Yoshida, Yuzo, Yamamoto, Shigeo, Hanioka, Nobumitsu
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 28.04.2006; Elsevier Science
• Subjects: 5-MeO-DIPT; 5-MeO-IPT; 5-Methoxytryptamine - analogs & derivatives; 5-Methoxytryptamine - metabolism; 5-OH-DIPT; Biological and medical sciences; CYP1A2; CYP2C8; CYP2D6; CYP3A4; Cytochrome P-450 Enzyme System - metabolism; Foxy; Humans; In Vitro Techniques; Medical sciences; Microsomes, Liver - enzymology; Oxidation-Reduction; Pharmacology. Drug treatments; Recombinant Proteins - metabolism; OR; 5-MeO-DIPT; 5-OH-DIPT; Foxy; CYP3A4; G-6-P; LC/MS; CYP2C8; CYP2D6; CYP1A2; 5-MeO-IPT; CYP; HPLC; PCR; Human; Digestive system; Enzyme; Isozyme; Cytochrome P450; Liver; Recombinant protein; Pharmacokinetics; Microsome; Metabolism; In vitro; Foxy 5-MeO-DIPT 5-OH-DIPT 5-MeO-IPT CYP2D6 CYP1A2 CYP2C8 CYP3A4
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2006.01.015

In vitro quantitative studies of the oxidative metabolism of (5-methoxy- N, N-diisopropyltryptamine, 5-MeO-DIPT, Foxy) were performed using human liver microsomal fractions and recombinant CYP enzymes and synthetic 5-MeO-DIPT metabolites. 5-MeO-DIPT was mainly oxidized to O-demethylated (5-OH-DIPT) and N-deisopropylated (5-MeO-IPT) metabolites in pooled human liver microsomes. In kinetic studies, 5-MeO-DIPT O-demethylation showed monophasic kinetics, whereas its N-deisopropylation showed triphasic kinetics. Among six recombinant CYP enzymes (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) expressed in yeast or insect cells, only CYP2D6 exhibited 5-MeO-DIPT O-demethylase activity, while CYP1A2, CYP2C8, CYP2C9, CYP2C19 and CYP3A4 showed 5-MeO-DIPT N-deisopropylase activities. The apparent K m value of CYP2D6 was close to that for 5-MeO-DIPT O-demethylation, and the K m values of other CYP enzymes were similar to those of the low- K m (CYP2C19), intermediate- K m (CYP1A2, CYP2C8 and CYP3A4) and high- K m phases (CYP2C9), respectively, for N-deisopropylation in human liver microsomes. In inhibition studies, quinidine (1 μM), an inhibitor of CYP2D6, almost completely inhibited human liver microsomal 5-MeO-DIPT O-demethylation at a substrate concentration of 10 μM. Furafylline, a CYP1A2 inhibitor, quercetin, a CYP2C8 inhibitor, sulfaphenazole, a CYP2C9 inhibitor and ketoconazole, a CYP3A4 inihibitor (5 μM each) suppressed about 60%, 45%, 15% and 40%, respectively, of 5-MeO-DIPT N-deisopropylation at 50 μM substrate. In contrast, omeprazole (10 μM), a CYP2C19 inhibitor, suppressed only 10% of N-deisopropylation by human liver microsomes, whereas at the same concentration the inhibitor suppressed the reaction by recombinant CYP2C19 almost completely. These results indicate that CYP2D6 is the major 5-MeO-DIPT O-demethylase, and CYP1A2, CYP2C8 and CYP3A4 are the major 5-MeO-DIPT N-deisopropylase enzymes in the human liver.