IC50: ~30 nM (recombinant hP2X3 homotrimers), 100-250 nM (hP2X2/3 heterotrimeric receptors)[1].

Gemfapic 柠檬酸盐不抑制任何含有非 P2X3 亚基的受体（重组同源三聚体 hP2X1、hP2X2、hP2X4、rP2X5 和 hP2X7 通道的 IC50 值 >10,000 nM）[1]。

在膝骨关节炎大鼠模型中（单碘乙酸关节内治疗后 14 天），枸橼酸 gemfapic（7 天，每日两次，口服）在两种较高剂量下均可减少负重偏侧性。完全逆转严重痛觉过敏[2]。

芳基嘧啶二胺，Gefapixant/AF-219 (Ford et al., 2013；Smith等人，2013)是一种口服活性的小分子（Mol Wt. ~ 350道尔顿）拮抗剂，用于人类含p2x3受体。据报道，af219对重组hP2X3三聚体的抑制效价（IC50）为~ 30 nM，对hP2X2/3异三聚体受体的抑制效价（IC50）为100-250 nM，与重组大鼠受体的抑制效价非常相似，并且对含有非p2x3亚基的受体没有抑制作用（在重组hP2X1， hP2X2, hP2X4， rP2X5和hP2X7通道的IC50值比10000 nM要高）。来自P2X3选择性嘧啶二胺类其他相关化学成员的报告表明，抑制机制是非竞争性的（变构），并且在P2X3受体效价估计的物种独立性方面存在混合：AF-353 （Gever等人，2010）在人类和大鼠重组P2X3三聚体之间显示出显著的效价一致性（IC50值分别为8.7和8.9 nM），而更有效的类似物AF-792(也称为RO-51；在一份报告中（Serrano等人，2012）显示，最初作为AF-353的潜在前药而开发的P2X3对人类和大鼠的P2X3受体的效力较弱，但在另一份报告中（Jahangir等人，2009）显示其与物种无关。值得注意的是，对P2X3和P2X3 /3通道的选择性是几种化学类抑制剂的共同主张（参见Gum等人，2012：例如AF-219类似物，核苷酸如TNP-ATP，苯三羧酸如a -317491），尽管在大多数研究中报告的值不是亲和力测定，而是IC50估计。在这种情况下，真正的选择性不能绝对推断，特别是对于竞争性拮抗剂（如TNP-ATP和a -317491），因为IC50是一个参数，它会随着使用的激动剂浓度而变化，并取决于激动剂在不同三聚体上的效力。[1]

Absorption
The absolute bioavailability of gefapixant has not been evaluated but is estimated to be ≥78%. At the recommended dose of 45 mg twice daily, steady-state is achieved within 2 days and the steady-state mean plasma AUC and Cmax are 4,144 ng∙hr/mL and 531 ng/mL, respectively. The time to peak plasma concentration (Tmax) following oral administration ranges from one to four hours. The co-administration of gefapixant with a high-fat, high-calorie meal had no effect on its AUC or Cmax.

Route of Elimination
Gefapixant is primarily eliminated via renal excretion. Following a single oral radiolabeled dose in a healthy male subject, approximately 76.4% of the administered radioactivity was recovered in the urine and 22.6% was recovered in the feces. Unchanged parent drug accounted for 64% of the recovered dose in the feces and accounted for 20% of the recovered dose in the urine.

Volume of Distribution
Based on population pharmacokinetic analyses, the estimated steady-state apparent volume of distribution is 133.8 L (Vc 101 L and Vp 32.8 L) following oral twice-daily administration of gefapixant 45 mg.

Clearance
Population pharmacokinetic analyses integrating data from Phase 1, 2, and 3 data showed a geometric mean apparent clearance (Cl/F) of 10.8 L/h. In clinical pharmacology studies, the observed clearance was 14.8 L/h and renal clearance was approximately 8.7 L/h.

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Metabolism / Metabolites
Gefapixant is relatively minimally metabolized. Following oral administration, only 14% of the administered dose was recovered as metabolites in the urine and feces. Unchanged parent drug is the major (87%) drug-related component in plasma, with circulating metabolites accounting for <10% each. The primary biotransformation pathways observed in gefapixant ADME studies included hydroxylation, O-demethylation, dehydrogenation, oxidation, and direct glucuronidation. Secondary biotransformation pathways included glucuronidation of O-demethylated metabolite as well as the formation of a metabolite that was O-demethylated and hydrogenated. The three most abundant circulating metabolites were: M1 (a glucuronide of O-demethylated gefapixant), M5 (a directly glucuronidated parent) and M13 (a hydroxylated metabolite.), which accounted for 1.0%, 6.3%, and 5.8%, respectively, of the total drug-related components in plasma.

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Biological Half-Life
The terminal half-life of gefapixant is 6-10 hours.

Protein Binding
Gefapixant exhibits relatively low protein binding (55%) _in vitro_, and thus drug-drug interactions resulting from protein displacement are not expected.

[1]. The therapeutic promise of ATP antagonism at P2X3 receptors in respiratory and urological disorders. Front Cell Neurosci. 2013; 7: 267.

[2]. Ford AP, In pursuit of P2X3 antagonists: novel therapeutics for chronic pain and afferent sensitization. Purinergic Signal. 2012 Feb;8(Suppl 1):3-26.

[3]. Validation of a visual analog scale for assessing cough severity in patients with chronic cough. Ther Adv Respir Dis. 2021 Jan-Dec;15:17534666211049743.

Drug Indication
Treatment of unexplained or chronic refractory cough

545.52

545.14

C, 44.04; H, 4.99; N, 12.84; O, 32.26; S, 5.88

2310299-91-1

Gefapixant;1015787-98-0

145720531

Solid powder

297

7

16

10

37

739

0

AIJVJYUOMCRFOE-UHFFFAOYSA-N

InChI=1S/C14H19N5O4S.C6H8O7/c1-7(2)8-4-10(22-3)12(24(17,20)21)5-9(8)23-11-6-18-14(16)19-13(11)15;7-3(8)1-6(13,5(11)12)2-4(9)10/h4-7H,1-3H3,(H2,17,20,21)(H4,15,16,18,19);13H,1-2H2,(H,7,8)(H,9,10)(H,11,12)

5-(2,4-diaminopyrimidin-5-yl)oxy-2-methoxy-4-propan-2-ylbenzenesulfonamide;2-hydroxypropane-1,2,3-tricarboxylic acid

Gefapixant citrate; MK-7264; MK 7264; Gefapixant citrate; DFK0FC2VVV; Gefapixant citrate [USAN]; 2310299-91-1; MK-7264; Gefapixant (citrate); UNII-DFK0FC2VVV; MK7264

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。