In Vitro Characterization and Pharmacokinetics of Dapagliflozin (BMS-512148), a Potent Sodium-Glucose Cotransporter Type II Inhibitor, in Animals and Humans
In Vitro Characterization and Pharmacokinetics of Dapagliflozin (BMS-512148), a Potent Sodium-Glucose Cotransporter Type II Inhibitor, in Animals and Humans
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DOI：
10.1124/dmd.109.029165
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发表时间：
2010-03-01
影响因子：
3.9
通讯作者：
Humphreys, W. G.
中科院分区：
文献类型：
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作者：
Obermeier, M.;Yao, M.;Humphreys, W. G.
(2S, 3R, 4R, 5S, 6R)-2-(3-(4-乙氧基苄基)-4-氯苯基)-6-羟甲基-四氢-2H-吡喃-3,4,5-三醇 (dapagliflozin; BMS-512148) 是一种有效的钠-葡萄糖协同转运蛋白 II 型抑制剂，适用于动物和 人类，目前正在开发用于治疗 2 型糖尿病。达格列净的临床前表征，以便在临床中进行化合物选择和药理学和处置行为预测，涉及 Caco-2 细胞渗透性研究、细胞色素 P450 (P450) 抑制和诱导研究、P450 反应表型、肝细胞中的代谢物鉴定以及大鼠、狗和猴子中的药代动力学。发现 Dapagliflozin 对 Caco-2 细胞膜具有良好的渗透性。人们发现它是 P-糖蛋白 (P-gp) 的底物，但不是重要的 P-gp 抑制剂。未发现达格列净是人类 P450 酶的抑制剂或诱导剂。与小鼠、大鼠、狗、猴子和人类的肝细胞一起孵育后，达格列净的体外代谢特征在性质上相似。大鼠肝细胞孵育显示出最高的周转率，而达格列净在人肝细胞中最稳定。观察到的主要体外代谢途径是葡萄糖醛酸化、羟基化和O-脱乙基化。达格列净在临床前物种中的药代动力学参数显示，该化合物具有足够的口服暴露、清除和消除半衰期，与人类每日单次给药的潜力一致。单剂量 50 mg [(14)C] 达格列净在人体中的药代动力学显示出良好的暴露、低清除率、足够的半衰期，并且没有具有显着药理活性或毒理学问题的代谢物。
(2S, 3R, 4R, 5S, 6R)-2-(3-(4-Ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyl- tetrahydro-2H-pyran-3,4,5-triol (dapagliflozin; BMS-512148) is a potent sodium-glucose cotransporter type II inhibitor in animals and humans and is currently under development for the treatment of type 2 diabetes. The preclinical characterization of dapagliflozin, to allow compound selection and prediction of pharmacological and dispositional behavior in the clinic, involved Caco-2 cell permeability studies, cytochrome P450 (P450) inhibition and induction studies, P450 reaction phenotyping, metabolite identification in hepatocytes, and pharmacokinetics in rats, dogs, and monkeys. Dapagliflozin was found to have good permeability across Caco-2 cell membranes. It was found to be a substrate for P-glycoprotein (P-gp) but not a significant P-gp inhibitor. Dapagliflozin was not found to be an inhibitor or an inducer of human P450 enzymes. The in vitro metabolic profiles of dapagliflozin after incubation with hepatocytes from mice, rats, dogs, monkeys, and humans were qualitatively similar. Rat hepatocyte incubations showed the highest turnover, and dapagliflozin was most stable in human hepatocytes. Prominent in vitro metabolic pathways observed were glucuronidation, hydroxylation, and O-deethylation. Pharmacokinetic parameters for dapagliflozin in preclinical species revealed a compound with adequate oral exposure, clearance, and elimination half-life, consistent with the potential for single daily dosing in humans. The pharmacokinetics in humans after a single dose of 50 mg of [(14)C] dapagliflozin showed good exposure, low clearance, adequate half-life, and no metabolites with significant pharmacological activity or toxicological concern.