title: LC-ESI-MS/MS analysis and pharmacokinetics of GP205, an innovative potent macrocyclic inhibitor of hepatitis C virus NS3/4A protease in rats.
abstract: A high-throughput, sensitive and specific LC-ESI-MS/MS method was established for the quantitative determination of GP205, a potent inhibitor of hepatitis C virus NS3/4A protease, in rat. The analyte was isolated from 25 μL plasma sample by 96-well LLE. Good linearity was achieved within the concentration range of 2-5000 ng/mL (r2 > 0.996). The intra- and inter-day precision was less than 10%. The accuracy ranged from 0.8% to 5.5% for GP205 in quality control samples at three levels. GP205 was stable during the analysis and the storage period. The method was successfully applied to pharmacokinetic studies of GP205 in Sprague-Dawley rats. The pharmacokinetic profiles of GP205 at three dose levels with oral administration and one dose level with intravenous administration were successfully studied for the first time in SD rats, respectively. After single oral administration of GP205 at the doses of 2.5, 5, 10 mg/kg, respectively, Cmax and AUC0-τ were proportional to the doses given. The absolute bioavailability was estimated as 34% based on the AUCs of oral administration at the dose of 5 mg/kg and intravenous administration at the dose of 1 mg/kg. The data presented in this study provides useful information for further study for GP205.
authors.affiliation: School of Pharmacy, Second Military Medical University, Shanghai 200433, China. luckyyangnan123@163.com.|Shanghai Key Laboratory for Pharmaceutical Metabolite Research, Shanghai 200433, China. luckyyangnan123@163.com.
authors.forename: Nan
authors.initials: N
authors.lastname: Yang
authors.affiliation: School of Pharmacy, Second Military Medical University, Shanghai 200433, China. sunnyautumn.cool@163.com.|Shanghai Key Laboratory for Pharmaceutical Metabolite Research, Shanghai 200433, China. sunnyautumn.cool@163.com.
authors.forename: Qiushi
authors.initials: Q
authors.lastname: Sun
authors.affiliation: School of Pharmacy, Second Military Medical University, Shanghai 200433, China. Xuzihua-668585@163.com.|Shanghai Key Laboratory for Pharmaceutical Metabolite Research, Shanghai 200433, China. Xuzihua-668585@163.com.
authors.forename: Zihua
authors.initials: Z
authors.lastname: Xu
authors.affiliation: School of Pharmacy, Second Military Medical University, Shanghai 200433, China. chunyuhan2012@163.com.|Shanghai Key Laboratory for Pharmaceutical Metabolite Research, Shanghai 200433, China. chunyuhan2012@163.com.|Fujian University of Traditional Chinese Medicine, Fuzhou 350108, China. chunyuhan2012@163.com.
authors.forename: Xiuyun
authors.initials: X
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Second Military Medical University, Shanghai 200433, China. yoyo0132@163.com.|Shanghai Key Laboratory for Pharmaceutical Metabolite Research, Shanghai 200433, China. yoyo0132@163.com.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.affiliation: School of Pharmacy, Second Military Medical University, Shanghai 200433, China. caoyuqing1109@163.com.|Shanghai Key Laboratory for Pharmaceutical Metabolite Research, Shanghai 200433, China. caoyuqing1109@163.com.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Ginkgo Pharma Co. Ltd., Suzhou 205125, China. chenli@ginkgopharma.com.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: School of Pharmacy, Second Military Medical University, Shanghai 200433, China. guorfan@outlook.com.|Shanghai Key Laboratory for Pharmaceutical Metabolite Research, Shanghai 200433, China. guorfan@outlook.com.
authors.forename: Guorong
authors.initials: G
authors.lastname: Fan
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002853:Chromatography, Liquid / Q000379:methods; D005260:Female; D047028:Macrocyclic Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D011480:Protease Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D053719:Tandem Mass Spectrometry / Q000379:methods; D014018:Tissue Distribution; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D047028:Macrocyclic Compounds; D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; C000604458:GP205 compound; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C093542:NS4 protein, hepatitis C virus