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1. Eur J Clin Pharmacol. 2012 May 15. [Epub ahead of print]

Effect of the CYP2C19 genotype on the pharmacokinetics of icotinib in healthy
male volunteers.

Ruan CJ, Liu DY, Jiang J, Hu P.

Clinical Pharmacology Research Center, Peking Union Medical College Hospital and
Chinese Academy of Medical Sciences, 1 Shuai Fu Yuan, Dong Chen District,
Beijing, 100730, China.

PURPOSE: Icotinib hydrochloride
{4-[(3-ethynylphenyl)amino]-6,7-benzo-12-crown-4-quinazoline hydrochloride}, a
novel epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI),
was designed for the treatment of non-small cell lung cancer (NSCLC). In the
present study, we investigated the influence of the CYP2C19*2 and CYP2C19*3
alleles on the pharmacokinetics of icotinib in healthy Chinese volunteers.
METHODS: In a single-dose pharmacokinetic study, 12 healthy Chinese volunteers
received an oral dose of 600 mg of icotinib. Plasma was sampled for up to 72 h
post-dose, followed by quantification of icotinib by liquid chromatography-mass
spectrometry/mass spectrometry (LC-MS-MS). RESULTS: Five subjects genotyped as
homozygous extensive metabolizers (CYP2C19*1/*1), 6 subjects genotyped as
heterozygous extensive metabolizers (CYP2C19*1/*2 or CYP2C19*1/*3), and 1 subject
genotyped as a poor metabolizer (CYP2C19*2/*3) and was withdrawn from the
research because of urticaria. The mean icotinib AUC(0-∞) and C(max) (14.56
±5.31 h mg/L and 2.32 ± 0.49 μg/mL) in homozygous EMs was 1.56 and 1.41-fold
lower than that in heterozygous EMs (22.7 ± 6.11 and 3.28 ± 0.48, P = 0.046 and
0.047). The mean CL/F (44.18 ± 12.17 L/h) in homozygous EMs was 1.55-fold higher
than that in heterozygous EMs (28.42 ± 9.23 L/h, P = 0.013). CONCLUSIONS: The
data showed that the pharmacokinetics of icotinib differ significantly between
homozygous EMs and heterozygous EMs in CYP2C19.

PMID: 22585284 [PubMed - as supplied by publisher]