Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania (D.A.B., D.B.M.-F., K.E.J., D.M.K., P.D.G., L.E.R.-P.); Department of Clinical Pharmacology Modeling and Simulation (D.O., N.N.) and Department of Oncology R&D (S.W.C.), GlaxoSmithKline, Research Triangle Park, North Carolina; Department of Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania (S.C.B., J.L.A.); and Comprehensive Clinical Development NW, Tacoma, Washington (R.A.M).
Drug Metab Dispos. 2013 Dec;41(12):2215-24. doi: 10.1124/dmd.113.053785. Epub 2013 Oct 4.
A phase I study was conducted to assess the metabolism and excretion of [(14)C]dabrafenib (GSK2118436; N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzene sulfonamide, methanesulfonate salt), a BRAF inhibitor, in four patients with BRAF V600 mutation-positive tumors after a single oral dose of 95 mg (80 µCi). Assessments included the following: 1) plasma concentrations of dabrafenib and metabolites using validated ultra-high-performance liquid chromatography--tandem mass spectrometry methods, 2) plasma and blood radioactivity, 3) urinary and fecal radioactivity, and 4) metabolite profiling. Results showed the mean total recovery of radioactivity was 93.8%, with the majority recovered in feces (71.1% of administered dose). Urinary excretion accounted for 22.7% of the dose, with no detection of parent drug in urine. Dabrafenib is metabolized primarily via oxidation of the t-butyl group to form hydroxy-dabrafenib. Hydroxy-dabrafenib undergoes further oxidation to carboxy-dabrafenib, which subsequently converts to desmethyl-dabrafenib via a pH-dependent decarboxylation. The half-lives for carboxy- and desmethyl-dabrafenib were longer than for parent and hydroxy-dabrafenib (18-20 vs. 5-6 hours). Based on area under the plasma concentration-time curve, dabrafenib, hydroxy-, carboxy-, and desmethyl-dabrafenib accounted for 11%, 8%, 54%, and 3% of the plasma radioactivity, respectively. These results demonstrate that the major route of elimination of dabrafenib is via oxidative metabolism (48% of the dose) and biliary excretion. Based on our understanding of the decarboxylation of carboxy-dabrafenib, a low pH-driven, nonenzymatic mechanism involving participation of the aryl nitrogen is proposed to allow prediction of metabolic oxidation and decarboxylation of drugs containing an aryl nitrogen positioned α to an alkyl (ethyl or t-butyl) side chain.
一项 I 期研究评估了单剂量 95 毫克（80μCi）口服后，BRAF V600 突变阳性肿瘤患者中 [(14)C]dabrafenib（GSK2118436；N-{3-[5-(2-氨基-4-嘧啶基)-2-(1,1-二甲基乙基)-1,3-噻唑-4-基]-2-氟苯基}-2,6-二氟苯磺酰胺，甲磺酸盐）的代谢和排泄情况。评估包括：1）采用经验证的超高效液相色谱-串联质谱法评估 dabrafenib 和代谢物的血浆浓度，2）血浆和血液放射性，3）尿和粪便放射性，4）代谢产物谱。结果显示，放射性总回收率的平均值为 93.8%，大部分在粪便中回收（占给药剂量的 71.1%）。尿液排泄占剂量的 22.7%，尿液中未检测到母体药物。Dabrafenib 主要通过叔丁基氧化形成羟基-dabrafenib 代谢。羟基-dabrafenib 进一步氧化形成羧基-dabrafenib，后者通过 pH 依赖性脱羧作用转化为去甲基-dabrafenib。羧基-dabrafenib 和去甲基-dabrafenib 的半衰期长于母体和羟基-dabrafenib（18-20 小时与 5-6 小时）。基于血浆浓度-时间曲线下面积，dabrafenib、羟基-dabrafenib、羧基-dabrafenib 和去甲基-dabrafenib 分别占血浆放射性的 11%、8%、54%和 3%。这些结果表明 dabrafenib 的主要消除途径是通过氧化代谢（占剂量的 48%）和胆汁排泄。基于我们对羧基-dabrafenib 脱羧作用的理解，提出了一种低 pH 驱动的、非酶促机制，涉及芳基氮的参与，以允许预测含有芳基氮位于α位的烷基（乙基或叔丁基）侧链的药物的代谢氧化和脱羧作用。
