Bhamidipati R, Mujeeb S, Dravid P V, Khan A A, Singh S K, Rao Y K, Mullangi R, Srinivas N R
Drug Metabolism and Pharmacokinetics, Discovery Research, Dr. Reddy's Laboratories Ltd, Miyapur, Hyderabad 500 049, India.
Xenobiotica. 2005 Mar;35(3):253-71. doi: 10.1080/00498250500066303.
The aim of this study was to characterize the pharmacokinetics and determine the absolute bioavailability and metabolism of DRF 4367, a novel COX-2 inhibitor, in mice. In addition, the in vitro metabolism of DRF 4367 was studied in mouse, rat, dog, monkey and human liver microsomes. Following oral administration, maximum concentrations of DRF 4367 were achieved after about 1 h. Upon intravenous (IV) administration, the concentration of DRF 4367 declined in a bi-exponential fashion with a terminal elimination half-life of 4.0 h. The elimination half-life was unchanged with route of administration. The volume of distribution and systemic clearance of DRF 4367 in mice were 0.80 l h(-1) kg(-1) and 0.14 l kg(-1), respectively, after IV administration. The absolute oral bioavailability of DRF 4367 was 44%. In all species of liver microsomes examined, the primary route of metabolism for DRF 4367 was demethylation of benzyl methoxy to form a hydroxy metabolite (M1). The formation of this metabolite was mediated by CYP2D6 and CYP2C19 enzymes. M1 was not found to possess COX-2 inhibitory activity. Chemical-inhibition studies showed that quinidine (selective for CYP2D6) and ticlopidine (selective for CYP2C19) inhibited the formation of the hydroxy metabolite of DRF 4367, whereas potent inhibitors selective for other forms of CYP did not inhibit this oxidative reaction. Upon oral or IV administration of DRF 4367 to mice, unchanged DRF 4367, M1, the O-glucuronide conjugate of M1 (M1-G) and the O-sulfate conjugate of M1 (M1-S) were identified in bile.
本研究旨在表征新型环氧化酶-2（COX-2）抑制剂DRF 4367在小鼠体内的药代动力学特征，确定其绝对生物利用度及代谢情况。此外，还研究了DRF 4367在小鼠、大鼠、犬、猴及人肝微粒体中的体外代谢。口服给药后，约1小时达到DRF 4367的最高浓度。静脉注射后，DRF 4367的浓度呈双指数下降，终末消除半衰期为4.0小时。消除半衰期不受给药途径影响。静脉注射后，DRF 4367在小鼠体内的分布容积和全身清除率分别为0.80 l h⁻¹ kg⁻¹和0.14 l kg⁻¹。DRF 4367的绝对口服生物利用度为44%。在所检测的所有物种肝微粒体中，DRF 4367的主要代谢途径是苄基甲氧基脱甲基形成羟基代谢物（M1）。该代谢物的形成由细胞色素P450 2D6（CYP2D6）和细胞色素P450 2C19（CYP2C19）酶介导。未发现M1具有COX-2抑制活性。化学抑制研究表明，奎尼丁（对CYP2D6有选择性）和噻氯匹定（对CYP2C19有选择性）抑制DRF 4367羟基代谢物的形成，而对其他形式CYP有选择性的强效抑制剂未抑制该氧化反应。给小鼠口服或静脉注射DRF 4367后，在胆汁中鉴定出未变化的DRF 4367、M1、M1的O-葡萄糖醛酸苷缀合物（M1-G）和M1的O-硫酸酯缀合物（M1-S）。
