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1. Drug Metab Dispos. 2012 Jan 31. [Epub ahead of print]

N-Isopropyl-p-iodoamphetamine Hydrochloride (IMP) is Predominantly Metabolized by
CYP2C19.

Fujita KI, Sugiyama M, Akiyama Y, Hioki K, Kunishima M, Nishi K, Kobayashi M,
Kawai K, Sasaki Y.

1 Saitama Medical University;

(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 (CYP) in the metabolism of non-radio-labeled 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, since 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 Km and Vmax of 8.6 μM and 9.7 nmol/min/nmol CYP,
respectively. 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. We thus demonstrated
that IMP was predominantly metabolized by CYP2C19 to form p-iodoamphetamine.

PMID: 22293120 [PubMed - as supplied by publisher]