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In search of the active metabolites of an anticancer piperazinedione, TW01003, in rats.

Wang CL, Chen CK, Wang YH, Cheng YW - Biomed Res Int (2014)

Bottom Line: Following intravenous administration of TW01003, pig urine samples were subjected to sulfatase and glucuronidase treatment to monitor the biotransformation products.Pharmacokinetic analysis after intravenous administration of TW01003 indicated that TW01003 sulfate had a systemic bioavailability 2.5 times higher, volume of distribution three times higher, residence time seven times longer, and clearance rate 2.3 times lower compared to TW01003.Our results indicate that the potent anticancer and antiangiogenesis activities of TW01003 might not come from TW01003 per se but from its metabolites TW01003 sulfate.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, No. 250, Wu-Hsing Street, Taipei 110, Taiwan.

ABSTRACT
TW01003, a piperazinedione derivative designed as an antimitotic agent, exhibited potent anticancer and antiangiogenesis activities in mice. However, oral administration of this compound in rats led to poor systemic bioavailability which suggested that in vivo efficacy might come from its metabolites. This report describes the identification of TW01003 metabolites in pig and Wistar rats. Following intravenous administration of TW01003, pig urine samples were subjected to sulfatase and glucuronidase treatment to monitor the biotransformation products. Rats were given TW01003 both intravenously and orally, and blood samples were collected and then analyzed by HPLC to quantitatively determine the metabolic transformation of TW01003 to its metabolite. A sulfate conjugate, TW01003 sulfate, was identified as the major metabolite for TW01003 after intravenous injection in both pig and rats. However, in rats, the glucuronide conjugate became major metabolite 30 min after TW01003 oral dosing. Pharmacokinetic analysis after intravenous administration of TW01003 indicated that TW01003 sulfate had a systemic bioavailability 2.5 times higher, volume of distribution three times higher, residence time seven times longer, and clearance rate 2.3 times lower compared to TW01003. Our results indicate that the potent anticancer and antiangiogenesis activities of TW01003 might not come from TW01003 per se but from its metabolites TW01003 sulfate.

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Structure of TW01003 in mice.
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fig1: Structure of TW01003 in mice.

Mentions: Tubulin binding agents, which result in mitotic arrest of tumor cell and then apoptosis, are now standard treatment in cancer chemotherapy [1–4]. (3E,6E)-3-Benzylidene-6-[(5-hydroxypyridin-2-yl)methylene]piperazine-2,5-dione (TW01003) (Figure 1), a piperazinedione derivative synthesized in this laboratory as an antimitotic agent, exhibited a broad spectrum of antitumor activities in 60 human disease-oriented cancer cell panel screenings [5–7]. A profound antiangiogenesis effect of this compound was demonstrated in mice; after oral treatment of TW01003 (3 mg/kg), the hemoglobin count of the matrigel with vascular endothelial growth factor- (VEGF-) induced angiogenesis was reduced to <1% (unpublished data). However, a preliminary pharmacokinetic study indicated poor bioavailability upon oral administration of this compound to rats, with only 1.72% of the oral fraction absorbed (unpublished data). This led to a suspicion that the potent antiangiogenesis effect of TW01003 might come from its metabolites.


In search of the active metabolites of an anticancer piperazinedione, TW01003, in rats.

Wang CL, Chen CK, Wang YH, Cheng YW - Biomed Res Int (2014)

Structure of TW01003 in mice.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4016869&req=5

fig1: Structure of TW01003 in mice.
Mentions: Tubulin binding agents, which result in mitotic arrest of tumor cell and then apoptosis, are now standard treatment in cancer chemotherapy [1–4]. (3E,6E)-3-Benzylidene-6-[(5-hydroxypyridin-2-yl)methylene]piperazine-2,5-dione (TW01003) (Figure 1), a piperazinedione derivative synthesized in this laboratory as an antimitotic agent, exhibited a broad spectrum of antitumor activities in 60 human disease-oriented cancer cell panel screenings [5–7]. A profound antiangiogenesis effect of this compound was demonstrated in mice; after oral treatment of TW01003 (3 mg/kg), the hemoglobin count of the matrigel with vascular endothelial growth factor- (VEGF-) induced angiogenesis was reduced to <1% (unpublished data). However, a preliminary pharmacokinetic study indicated poor bioavailability upon oral administration of this compound to rats, with only 1.72% of the oral fraction absorbed (unpublished data). This led to a suspicion that the potent antiangiogenesis effect of TW01003 might come from its metabolites.

Bottom Line: Following intravenous administration of TW01003, pig urine samples were subjected to sulfatase and glucuronidase treatment to monitor the biotransformation products.Pharmacokinetic analysis after intravenous administration of TW01003 indicated that TW01003 sulfate had a systemic bioavailability 2.5 times higher, volume of distribution three times higher, residence time seven times longer, and clearance rate 2.3 times lower compared to TW01003.Our results indicate that the potent anticancer and antiangiogenesis activities of TW01003 might not come from TW01003 per se but from its metabolites TW01003 sulfate.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, No. 250, Wu-Hsing Street, Taipei 110, Taiwan.

ABSTRACT
TW01003, a piperazinedione derivative designed as an antimitotic agent, exhibited potent anticancer and antiangiogenesis activities in mice. However, oral administration of this compound in rats led to poor systemic bioavailability which suggested that in vivo efficacy might come from its metabolites. This report describes the identification of TW01003 metabolites in pig and Wistar rats. Following intravenous administration of TW01003, pig urine samples were subjected to sulfatase and glucuronidase treatment to monitor the biotransformation products. Rats were given TW01003 both intravenously and orally, and blood samples were collected and then analyzed by HPLC to quantitatively determine the metabolic transformation of TW01003 to its metabolite. A sulfate conjugate, TW01003 sulfate, was identified as the major metabolite for TW01003 after intravenous injection in both pig and rats. However, in rats, the glucuronide conjugate became major metabolite 30 min after TW01003 oral dosing. Pharmacokinetic analysis after intravenous administration of TW01003 indicated that TW01003 sulfate had a systemic bioavailability 2.5 times higher, volume of distribution three times higher, residence time seven times longer, and clearance rate 2.3 times lower compared to TW01003. Our results indicate that the potent anticancer and antiangiogenesis activities of TW01003 might not come from TW01003 per se but from its metabolites TW01003 sulfate.

Show MeSH
Related in: MedlinePlus