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01-04-2008 | PRECLINICAL STUDIES

Biotransformation and pharmacokinetics of the novel anticancer drug, SYUIQ-5, in the rat

Authors: Qi-Biao Su, Fan He, Xue-Ding Wang, Su Guan, Zhi-Yong Xie, Lai-You Wang, Yu-Jing Lu, Lian-Quan Gu, Zhi-Shu Huang, Xiao Chen, Min Huang, Shu-Feng Zhou

Published in: Investigational New Drugs | Issue 2/2008

Summary

SYUIQ-5, a novel telomerase inhibitor, has demonstrated antitumor activity in nude mouse studies. The objective of the present study was to examine the metabolism and pharmacokinetics of SYUIQ-5 in rats. The plasma pharmacokinetics of SYUIQ-5 was nonlinear following i.p. administration at 15, 30 and 60 mg/kg. SYUIQ-5 metabolism in rat liver microsomes followed Michaelis-Menten kinetics, with K _m and V_max values of 12.3 μM and 2.01 nmol/min/mg protein, respectively. Ketoconazole significantly inhibited the metabolism of SYUIQ-5 in liver microsomes from rats pretreated with control vehicle or various inducers, whereas sulphaphenazole, ticlopidine, quinidine, and methylpyrazole had no inhibitory effects on SYUIQ-5 metabolism. Dexamethasone and β-naphthoflavone (BNF), but not phenobarbital and ethanol, significantly induced SYUIQ-5 metabolism in rats. α-Naphthoflavone significantly inhibited SYUIQ-5 metabolism in liver microsomes from BNF-pretreated rats. Similar to other secondary amines, SYUIQ-5 underwent N-demethylation and O-oxygenation to at least two metabolites by rat liver microsomes. Pretreatment of rats with SYUIQ-5 at 0.1, 5 or 10 mg/kg for 5 days significantly induced the expression and activity of rat Cyp1A1/2, and induced Cyp3A1/2 expression at 10 mg/kg, but not Cyp2E1 and 2B1/2. These results indicate that that SYUIQ-5 exhibits dose-dependent pharmacokinetics in rats and it is mainly metabolized by Cyp3A1/2.

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Title: Biotransformation and pharmacokinetics of the novel anticancer drug, SYUIQ-5, in the rat
Authors: Qi-Biao Su
Fan He
Xue-Ding Wang
Su Guan
Zhi-Yong Xie
Lai-You Wang
Yu-Jing Lu
Lian-Quan Gu
Zhi-Shu Huang
Xiao Chen
Min Huang
Shu-Feng Zhou
Publication date: 01-04-2008
Publisher: Springer US
Published in: Investigational New Drugs / Issue 2/2008
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-007-9089-9

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