title: Application of an ultra-performance liquid chromatography method with tandem mass spectrometry to pharmacokinetics, tissue distribution and excretion in the study of DAT-230, a novel tubulin-binding agent candidate, in rats.
abstract: A rapid, sensitive and high-throughput ultra-performance liquid chromatography method with tandem mass spectrometry (UPLC-MS/MS) has been developed for the determination of DAT-230 in rat plasma, urine, feces and tissues (heart, liver, spleen, lung, kidney, stomach, intestine and brain). The biological samples were prepared by protein precipitation, and separation was achieved on an ACQUITY™ UPLC BEH C18 column (50 mm × 2.1mm, 1.7 μm) with a mobile phase that consisted of methanol - 0.2% formic acid water (80:20, v/v) at a flow rate of 0.2 mL/min. The MS/MS ion transitions were monitored at m/z 372.17 → 357.17 for DAT-230 and m/z 406.08 → 345.16 for COH-203 (internal standard, IS). The calibration curve was linear in the range of 0.1-5200 ng/mL for all biological matrices (r(2) ≥ 0.996), and it had the same value for the lower limit of quantification. The validated method was successfully applied to the pharmacokinetics, tissue distribution and excretion study after intravenous administration of a 5mg/kg dose of DAT-230 to healthy Sprague-Dawley rats. The mean pharmacokinetic parameters of t1/2 and AUC0-12 were (1.1 ± 0.4)h and (861.0 ± 281.2) ng h/mL, respectively. Tissue distribution results indicated that DAT-230 exhibited rapid distribution and high liver, kidney, spleen, stomach and intestine uptake; these organs were indicated as the major target organs of the drug. In total, 5.3% of the administered DAT-230 was excreted in an unconverted form in urine, feces and bile, which implies that DAT-230 was excreted primarily in the form of metabolites.
authors: School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang 110016, China.
authors: Jingya
authors: J
authors: Tang
authors: School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang 110016, China.
authors: Chungang
authors: C
authors: Zhang
authors: Department of Medicinal Chemistry, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang 110016, China.
authors: Jun
authors: J
authors: Sun
authors: School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang 110016, China.
authors: Longshan
authors: L
authors: Zhao
authors: Department of Medicinal Chemistry, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang 110016, China.
authors: Weige
authors: W
authors: Zhang
authors: School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang 110016, China.
authors: Zhenzhen
authors: Z
authors: Liu
authors: School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang 110016, China. Electronic address: lisunlu@126.com.
authors: Lu
authors: L
authors: Sun
authors: School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang 110016, China. Electronic address: cxh_syphu@hotmail.com.
authors: Xiaohui
authors: X
authors: Chen
mesh_terms: D000814:Aniline Compounds / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000818:Animals; D019540:Area Under Curve; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D002138:Calibration; D002853:Chromatography, Liquid / Q000379:methods* / Q000592:standards; D005243:Feces / Q000737:chemistry; D006207:Half-Life; D065669:Hepatobiliary Elimination; D057166:High-Throughput Screening Assays / Q000592:standards; D007275:Injections, Intravenous; D066237:Intestinal Elimination; D016014:Linear Models; D008297:Male; D008657:Metabolic Clearance Rate; D017207:Rats, Sprague-Dawley; D012015:Reference Standards; D065667:Renal Elimination; D015203:Reproducibility of Results; D053719:Tandem Mass Spectrometry / Q000379:methods* / Q000592:standards; D013876:Thiophenes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D014018:Tissue Distribution; D050257:Tubulin Modulators / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
chemical_list: C575717:2-methoxy-5-(2-(3,4,5-trimethoxyphenyl)thiophen-3-yl)aniline; D000814:Aniline Compounds; D013876:Thiophenes; D050257:Tubulin Modulators
keywords: DAT-230; Excretion; Pharmacokinetics; Tissue distribution; UPLC/MS/MS