title: In search of the active metabolites of an anticancer piperazinedione, TW01003, in rats.
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.
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, No. 250, Wu-Hsing Street, Taipei 110, Taiwan.
authors.forename: Chun-Li
authors.initials: CL
authors.lastname: Wang
authors.affiliation: Research and Development Center, United Biomedical, Inc., Asia, No. 45, Guangfu N. Road, Hukou, Hsinchu 303, Taiwan.
authors.forename: Ching-Kuei
authors.initials: CK
authors.lastname: Chen
authors.affiliation: Department of Nursing, Yuanpei University, No. 306, Yuanpei Street, Xiangshan District, Hsinchu 300, Taiwan.
authors.forename: Yao-Horng
authors.initials: YH
authors.lastname: Wang
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, No. 250, Wu-Hsing Street, Taipei 110, Taiwan.
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Cheng
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D001711:Biotransformation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D054659:Diketopiperazines / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D008297:Male; D010879:Piperazines / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D017208:Rats, Wistar; D034421:Sus scrofa; D013997:Time Factors
chemical_list: C000594601:3-benzylidene-6-((5-hydroxypyridin-2-yl)methylene)piperazine-2,5-dione; D000970:Antineoplastic Agents; D054659:Diketopiperazines; D010879:Piperazines