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- Title
Biotransformation and pharmacokinetics of the novel anticancer drug, SYUIQ-5, in the rat.
- Authors
Qi-Biao Su; 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
- Abstract
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 Vmax 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.
- Subjects
BIOCHEMISTRY; CHEMISTRY; BIOLOGY; MEDICAL sciences
- Publication
Investigational New Drugs, 2008, Vol 26, Issue 2, p119
- ISSN
0167-6997
- Publication type
Article
- DOI
10.1007/s10637-007-9089-9