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Xenobiotica. 2017 Aug;47(8):667-672. doi: 10.1080/00498254.2016.1217365. Epub 2017 Jan 12.

Identification of cytochrome P450s involved in the metabolism of 6-benzyl-1-benzyloxymethyl-5-iodouracil (W-1) using human recombinant enzymes and rat liver microsomes in vitro.

Author information

1
a Department of Pharmacology , School of Basic Medical Science, Beijing (Peking) University , Beijing , PR China.
2
b Department of Chemical Biology , School of Pharmaceutical Sciences, Beijing (Peking) University , Beijing , PR China.
3
c State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Beijing (Peking) University , Beijing , PR China , and.
4
d Department of Drug Metabolism & Pharmacokinetics , Biogen , Cambridge , MA , USA.

Abstract

1. The aim of this study was to identify the hepatic metabolic enzymes, which involved in the biotransformation of 6-benzyl-1-benzyloxymethyl-5-iodouracil (W-1), a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) in rat and human in vitro. 2. The parent drug of W-1 was incubated with rat liver microsomes (RLMs) or recombinant CYPs (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5, respectively) in the presence or absence of nicotinamide adeninedinucleotide phosphate (NADPH)-regenerating system. The metabolites of W-1 were analyzed with liquid chromatography-ion trap-time of flight-mass spectrometry (LC-IT-TOF-MS). 3. The parent drug of W-1 was metabolized in a NADPH-dependent manner in RLMs. The kinetic parameters of prototype W-1 including Km, Vmax, and CLint were 2.3 μM, 3.3 nmol/min/mg protein, and 1.4 mL/min/mg protein, respectively. Two metabolites M1 and M2 were observed in shorter retention times (2.988 and 3.188 min) with a higher molecular ion at m/z 463.0160 (both M1 and M2) than that of the W-1 parent drug (6.158 min with m/z 447.0218). The CYP selective inhibition and recombinant enzymes also showed that two hydroxyl metabolites M1 and M2 are mainly mediated by CYP2C19 and CYP3A4. 4. The identification of CYPs involved in W-1 biotransformation is important to understand and minimize, if possible, the potential of drug-drug interactions.

KEYWORDS:

6-benzyl-1-benzyloxymethyl-5-iodouracil (W-1); Human recombinant cytochrome P450; liquid chromatography-ion trap-time of flight-mass spectrometry (LC-IT-TOF-MS); metabolism in vitro; rat liver microsomes

PMID:
27910729
DOI:
10.1080/00498254.2016.1217365
[Indexed for MEDLINE]

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