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.

Determination of SYUIQ-F5, a Novel Telomerase Inhibitor and Anti-tumor Lead-Compound, in Tissues and Plasma Samples by LC–MS–MS: Application to a Tissue Distribution Study in Rat

“…Similar effects are also observed in leukemia cells [9]. These three quindoline derivatives have demonstrated substantial antitumor activity in nude mouse studies and the biotransformation and pharmacokinetics of SYUIQ-5 have been clearly described in our previously published paper [5]. SYUIQ-F5 was modified from SYUIQ-5.…”

“…1) is a novel quindoline derivative synthesized by the School of Pharmaceutical Sciences, Sun Yat-sen University. SYUIQ-F5 has been shown to interfere with telomere replication by blocking the elongation step catalyzed by both telomerasedependent and telomerase-independent mechanisms like its homologues such SYUIQ-5 and SYUIQ-FM05, which were also synthesized by Sun Yat-sen University [1][2][3][4][5]. Considerable evidence suggested that stabilization of G-quadruplex structures could directly inhibit telomerase activity and might cause down-regulation for the transcription of some oncogenes including G-quadruplex forming sequence in their promoters, such as bcl-2, c-myc, and c-kit [1,[6][7][8].…”

“…Considerable evidence suggested that stabilization of G-quadruplex structures could directly inhibit telomerase activity and might cause down-regulation for the transcription of some oncogenes including G-quadruplex forming sequence in their promoters, such as bcl-2, c-myc, and c-kit [1,[6][7][8]. Multiple experimental results indicated that treatment with these quindoline derivatives, such as SYUIQ-5 and SYUIQ-FM05, the homologues of SYUIQ-F5, could inhibit telomerase activity in human leukemia K562 cells and colon cancer SW620 cells, induce a marked cessation in cell growth and cellular senescence accompanied by a shortening of telomere length and induction of p16, p21, and p27 proteins, down-regulate the transcription of c-myc in human lymphoma Ramos and CA46 cells, turn off the transcription of bcl-2 in human leukemia HL-60 cells and thus facilitate cancer cell apoptosis [1][2][3][4][5]. Similar effects are also observed in leukemia cells [9].…”

Stabilization of VEGF G-quadruplex and inhibition of angiogenesis by quindoline derivatives

“…Cyp3A is the primary enzyme involved in SYUIQ-5 metabolism in rat liver microsomes. SYUIQ-5 induces the mRNA and protein of rat Cyp1A1 and 1A2 in a dose-dependent manner, while SYUIQ-5 does not affect the expression and activity of Cyp2B1/2 and 2E1 [42]. SYUIQ-5 has also demonstrated substantial antitumor activity in nude mouse studies (unpublished data, Huang et al).…”

Regulation of CYP1A1 by heavy metals and consequences for drug metabolism

“…Newer agents, including SYUIQ-5 [172] and AQ4N, are also metabolized by CYP1A1. Like many other chemotherapeutic agents, AQ4N is activated through metabolic processes.…”