临床前的物种和人类性格的pf - 04971729,一种选择性抑制剂sodium-dependent葡萄糖转运蛋白2和临床治疗2型糖尿病的候选人。

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朱Kalgutkar, Tugnait M, T, Kimoto E,苗族Z, Mascitti V,杨X,谭B, Walsky RL, Chupka J,冯B,罗宾逊RP

临床前的物种和人类性格的pf - 04971729,一种选择性抑制剂sodium-dependent葡萄糖转运蛋白2和临床治疗2型糖尿病的候选人。

药物金属底座Dispos。2011年9月,39(9):1609 - 19所示。doi: 10.1124 / dmd.111.040675。Epub 2011 6月20。

PubMed ID

21690265 (在PubMed

]

文摘

(1 s, 2 s, 3 s, 4 r, 5 s) 5 - [4-Chloro-3 - (4-ethoxybenzyl)苯基]1-hydroxymethyl-6, 8-dioxab icyclo (3.2.1) octane-2, 3, 4-triol (pf - 04971729),一个强有力的和sodium-dependent葡萄糖转运蛋白2的选择性抑制剂,目前在第二阶段试验治疗糖尿病。本文描述了临床体外人类物种和性格特征的pf - 04971729用于实验支持first-in-human进行研究。老鼠的等离子体间隙很低(4.04毫升。分钟(1)。公斤(1))和狗(1.64毫升。分钟(1)。公斤(1)),导致半衰期分别为4.10和7.63 h。老鼠的中度至良好的生物利用度(69%)和口服给药后观察狗(94%)。体外生物转化概要的pf - 04971729肝微粒体和低温贮藏肝细胞从老鼠,狗和人类是定性相似;著名的代谢途径包括monohydroxylation, O-deethylation, glucuronidation。 No human-specific metabolites of PF-04971729 were detected in in vitro studies. Reaction phenotyping studies using recombinant enzymes indicated a role of CYP3A4/3A5, CYP2D6, and UGT1A9/2B7 in the metabolism of PF-04971729. No competitive or time-dependent inhibition of the major human cytochrome P450 enzymes was discerned with PF-04971729. Inhibitory effects against the organic cation transporter 2-mediated uptake of [(14)C]metformin by PF-04971729 also were very weak (IC(50) = approximately 900 muM). Single-species allometric scaling of rat pharmacokinetics of PF-04971729 was used to predict human clearance, distribution volume, and oral bioavailability. Human pharmacokinetic predictions were consistent with the potential for a low daily dose. First-in-human studies after oral administration indicated that the human pharmacokinetics/dose predictions for PF-04971729 were in the range that is likely to yield a favorable pharmacodynamic response.

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