中国药理学通报2012，Vol.28Issue(7)：1010-1014,5.DOI:10.3969/j.issn.1001-1978.2012.07.029
四氢小檗红碱及其前药的比格犬药代动力学研究
Pharmacokinetic study of tetrahydroberberrabine and its prodrug in Beagle dogs
摘要
Abstract
Aim To develop a LC-MS/MS method for simultaneous quantification of tetrahydroberberrabine (THB) and its prodrug, 9-acetyl tetrahydroberberrabine sulfate (ATHBS) , and to investigate their phar-macokinetic profiles in Beagle dogs. Method Blood concentrations of ATHBS and THB were measured with a validated LC-MS/MS method. Blood-time profiles of THB were determined in Beagle dogs after a single intravenous or oral dose of ATHBS (3 mg · kg-1 ). The pharmacokinetic parameters were obtained with the Wi -nNonlin software. Result A good linearity was observed over the concentration range of 2 ~ 2 000 μg · L-1 ( r > 0. 9985 ) with the lower limit of quantification at 2 μg· L-1 for both ATHBS and THB. The recoveries were more than 78. 74% and 75. 52% for THB and ATHBS, respectively. The intra and inter-day precisions (RSD) were all within 10.79% and the assay accuracies ( RE) ranged from - 10. 30% ~ 3. 92%. The results of the pharmacokinetic study indicated that ATHBS could be converted into its active metaboliteTHB very rapidly in Beagle dogs after oral and intrave -nous administrations. Intravenous THB reached the blood peak of (605. 99 ±102. 88) μg · L-1 at 2 min, followed by a biphasic decline. T1/2 was (7. 03 ± 1. 77 )hand AUC(0-1) was(718. 64 ± 143. 01) h · μg· L-1. For oral administration, the Cmax, of THB (77.71 ± 26. 60)μg· L was observed at 15 min and a second smaller peak was detected at 6h post-dose. T1/2 was (5. 89 ±3. 95)h and AUC(0-1) was(179. 62 ±91. 64)h · μg· L . The oral bioavailability calculated as THB was 26.2%. Conclusion The LC-MS/MS method is proved to be simple , sensitive and rapid. It has been successfully used for the pharmacokinetic study in dog . ATHBS can be metabolized rapidly in dog to release its active component THB, which quickly appears in blood. The oral bioavailability of THB was moderate.关键词
四氢小檗红碱/前药/药代动力学/生物利用度/LC-MS/MS/比格犬Key words
tetrahydroberberrabine / prodrug/ phar-macokinetics/ bioavailability/ LC-MS/MS/ Beagle dog分类
医药卫生引用本文复制引用
彭真珍,原梅,温泉,李桦,赵春杰,杨征..四氢小檗红碱及其前药的比格犬药代动力学研究[J].中国药理学通报,2012,28(7):1010-1014,5.基金项目
国家科技重大专项重大新药创制项目(No 2008ZXJ09004-033,2009ZX09301-002) （No 2008ZXJ09004-033,2009ZX09301-002）
