title: Biotransformation and pharmacokinetics of the novel anticancer drug, SYUIQ-5, in the rat.
abstract: 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 Km and Vmax values of 12.3 microM 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 beta-naphthoflavone (BNF), but not phenobarbital and ethanol, significantly induced SYUIQ-5 metabolism in rats. Alpha-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.
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, and Department of Pharmacy, Guangzhou Children's Hospital, Guangzhou, China.
authors.forename: Qi-Biao
authors.initials: QB
authors.lastname: Su
authors.forename: Fan
authors.initials: F
authors.lastname: He
authors.forename: Xue-Ding
authors.initials: XD
authors.lastname: Wang
authors.forename: Su
authors.initials: S
authors.lastname: Guan
authors.forename: Zhi-Yong
authors.initials: ZY
authors.lastname: Xie
authors.forename: Lai-You
authors.initials: LY
authors.lastname: Wang
authors.forename: Yu-Jing
authors.initials: YJ
authors.lastname: Lu
authors.forename: Lian-Quan
authors.initials: LQ
authors.lastname: Gu
authors.forename: Zhi-Shu
authors.initials: ZS
authors.lastname: Huang
authors.forename: Xiao
authors.initials: X
authors.lastname: Chen
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.forename: Shu-Feng
authors.initials: SF
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003959:Diamines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D007274:Injections, Intraperitoneal; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism; D011804:Quinolines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D019098:Telomerase / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D003959:Diamines; D008565:Membrane Proteins; C521094:N'-(10H-indolo(3,2-b)quinolin-11-yl)-N,N-dimethylpropane-1,3-diamine; D011804:Quinolines; D001189:Aryl Hydrocarbon Hydroxylases; C465260:Cyp3a2 protein, rat; C465138:Cyp3a23-3a1 protein, rat; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; D019098:Telomerase