Marques Lucas M M, Callejon Daniel R, Pinto Larissa G, de Campos Michel L, de Oliveira Anderson R M, Vessecchi Ricardo, Adhikari Achyut, Shrestha Ram L S, Peccinini Rosangela G, Lopes Norberto P
Departamento de Físico-Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, 14040-903 Ribeirão Preto, São Paulo, Brazil.
Departamento de Físico-Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, 14040-903 Ribeirão Preto, São Paulo, Brazil; Wolfson Centre for Age-Related Diseases, Kings College London, Guy's Campus, London Bridge, SE11UL-London, England.
J Pharm Biomed Anal. 2016 Nov 30;131:464-472. doi: 10.1016/j.jpba.2016.09.003. Epub 2016 Sep 3.
Govaniadine (GOV) is an alkaloid isolated from Corydalis govaniana Wall. It has been reported to show a different number of biological activities including anti-urease, leishmanicidal and antinociceptive. The present study aims to characterize the GOV in vitro metabolism after incubation with rat and human liver microsomes (RLM and HLM, respectively) and to evaluate its pharmacokinetic properties. The identification of GOV metabolites was conducted by different mass analyzers: a micrOTOF II-ESI-ToF Bruker Daltonics and an amaZon-SL ion trap (IT) Bruker Daltonics. For the pharmacokinetic study of GOV in rats after intravenous administration, a LC-MS/MS method was developed and applied to. The analyses were performed using an Acquity UPLC coupled to an Acquity TQD detector equipped with an ESI interface. The liver microsomal incubation resulted in new O-demethylated, di-hydroxylated and mono-hydroxylated compounds. Regarding the method validation, the calibration curve was linear over the concentration range of 2.5-3150.0ngmL, with a lower limit of quantitation (LLOQ) of 2.5ngmL. This method was successfully applied to a pharmacokinetic study. The profile was best fitted to a two-compartment model, the first phase with a high distribution rate constant (α) 0.139±0.086min, reflected by the short distribution half-life (t1/2α) 9.2±8.9min and the later one, with an elimination half-life (t1/2β) 55.1±37.9min. The main plasma protein binding was 96.1%. This is a first report in this field and it will be useful for further development of govaniadine as a drug candidate.
戈瓦尼定（GOV）是从高氏紫堇（Corydalis govaniana Wall.）中分离出的一种生物碱。据报道，它具有多种生物活性，包括抗脲酶、抗利什曼原虫和镇痛作用。本研究旨在分别与大鼠和人肝微粒体（RLM和HLM）孵育后，对GOV的体外代谢进行表征，并评估其药代动力学性质。通过不同的质量分析仪对GOV代谢物进行鉴定：一台布鲁克道尔顿公司的micrOTOF II-ESI-ToF和一台布鲁克道尔顿公司的amaZon-SL离子阱（IT）。为了研究GOV静脉注射后在大鼠体内的药代动力学，开发并应用了一种LC-MS/MS方法。分析使用的是一台与配备ESI接口的Acquity TQD检测器联用的Acquity UPLC。肝微粒体孵育产生了新的O-去甲基化、二羟基化和单羟基化化合物。关于方法验证，校准曲线在2.5-3150.0ng/mL的浓度范围内呈线性，定量下限（LLOQ）为2.5ng/mL。该方法成功应用于药代动力学研究。该曲线最适合二室模型，第一相具有较高的分布速率常数（α）0.139±0.086min，分布半衰期（t1/2α）为9.2±8.9min，后期为消除半衰期（t1/2β）55.1±37.9min。主要血浆蛋白结合率为96.1%。这是该领域的首次报道，将有助于戈瓦尼定作为候选药物的进一步开发。
