title: N-Isopropyl-p-iodoamphetamine hydrochloride Is predominantly metabolized by CYP2C19.
abstract: [(123)I]N-Isopropyl-p-iodoamphetamine hydrochloride ([(123)I]IMP) is clinically used to evaluate blood flow in the brain on single photon emission-computed tomography. This is a rare radiopharmaceutical that undergoes metabolism. The first step is reported to be [(123)I]p-iodoamphetamine formation. The drug-metabolizing enzyme(s) involved remain(s) unclear. This study examined the roles of human cytochrome P450 (P450) in the metabolism of nonradiolabeled IMP with the use of human liver microsomes (HLM) and recombinant human CYP1A1, -1A2, -1B1, -2A6, -2B6, -2C8, -2C9, -2C19, -2D6, -2E1, -3A4, and -3A5. Disappearance of IMP was examined because p-iodoamphetamine was not available. IMP (0.5 μM) time-dependently disappeared when HLM and NADPH-generating system were added to the reaction mixture. (S)-Mephenytoin (1 mM) inhibited the IMP disappearance by approximately 90%. The disappearance of IMP was predominantly catalyzed by recombinant CYP2C19, with K(m) and V(max) of 8.6 μM and 9.7 nmol · min(-1) · nmol P450(-1), respectively. IMP disappearance in CYP2C19-deficient HLM (CYP2C19*2/*2) was approximately 30% of that in the presence of HLM harboring wild-type CYP2C19, indicating that IMP is polymorphically metabolized by CYP2C19. High-performance liquid chromatography of the incubation mixture of IMP and CYP2C19 revealed an unidentified peak. As the area of the IMP peak decreased, the area of this unidentified peak increased in a time-dependent fashion. The peak was also detectable on incubation of IMP with HLM. Mass spectrometry revealed that the molecular weight of a compound in this unidentified peak was the same as that of p-iodoamphetamine. Thus, we demonstrated that IMP was predominantly metabolized by CYP2C19 to form p-iodoamphetamine.
authors.affiliation: Department of Medical Oncology, International Medical Center-Comprehensive Cancer Center, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama 350-1298, Japan. fujitak@saitama-med.ac.jp
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Fujita
authors.forename: Minako
authors.initials: M
authors.lastname: Sugiyama
authors.forename: Yuko
authors.initials: Y
authors.lastname: Akiyama
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Hioki
authors.forename: Munetaka
authors.initials: M
authors.lastname: Kunishima
authors.forename: Kodai
authors.initials: K
authors.lastname: Nishi
authors.forename: Masato
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kawai
authors.forename: Yasutsuna
authors.initials: Y
authors.lastname: Sasaki
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D065731:Cytochrome P-450 CYP2C19; D006801:Humans; D066298:In Vitro Techniques; D020367:Iofetamine / Q000378:metabolism*; D007700:Kinetics; D008862:Microsomes, Liver / Q000201:enzymology* / Q000378:metabolism; D019275:Radiopharmaceuticals / Q000378:metabolism*; D021241:Spectrometry, Mass, Electrospray Ionization; D013997:Time Factors
chemical_list: D019275:Radiopharmaceuticals; D020367:Iofetamine; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19