GLP-1 receptor

体外活性：阿必鲁肽是一种小蛋白质/肽，由两个拷贝的修饰人 GLP-1（片段 7-36）的 30 个氨基酸序列组成，用甘氨酸取代 8 位天然存在的丙氨酸进行修饰。以增强对 DPP-4 的抵抗力。

单剂量阿必鲁肽后，由于该分子与 GLP-1 受体结合，24 小时内就会产生降血糖作用。空腹和餐后血糖水平的降低与剂量相关。阿必鲁肽的效力不如 GLP-1。在糖尿病动物模型中，阿必鲁肽给药可刺激 β 细胞质量增加。 2型糖尿病患者皮下注射单次30毫克剂量后，3-5天内达到最大浓度，半衰期为3.6-6.8天。单剂量阿必鲁肽后的表观分布容积为8.2-18.5 L。阿必鲁肽在循环中的最终命运是降解成小肽和单个氨基酸。阿必鲁肽对雄性食蟹猴的心血管功能、心率、心电图间隔或呼吸功能没有明显影响，并且没有产生任何心电图异常或心律失常的证据。此外，对神经行为功能评估没有阿必鲁肽相关的影响。阿必鲁肽不会穿过血脑屏障到达饱腹感中枢。阿必鲁肽可减少心肌梗死面积，改善心肌 I/R 损伤后的心脏功能和能量学，这与心肌葡萄糖摄取增强以及通过增加葡萄糖和乳酸氧化向更有利的底物代谢转变有关。

Maximum concentrations of albiglutide were reached at 3 to 5 days post-dosing following a single 30mg dose. The mean peak concentration (Cmax) and mean area under the time-concentration curve (AUC) of albiglutide were 1.74 mcg/mL and 465 mcg.h/mL, respectively
11 L.
67 mL/h.
/MILK/ It is not known whether albiglutide is distributed into milk in humans ... .
Albiglutide is a glucagon-like peptide-1 analogue composed of tandem copies of modified human glucagon-like peptide-1 (7-36) coupled to recombinant human albumin that is approved in adults for the treatment of type 2 diabetes mellitus. After subcutaneous administration, albiglutide is likely primarily absorbed via the lymphatic circulation, with maximum concentrations being reached in 3 to 5 days; steady-state exposures are achieved following approximately 4 to 5 weeks of once-weekly administration. The elimination half-life of albiglutide is approximately 5 days. Clearance of albiglutide is 67 mL/h with between-subject variability of 34.9%; no covariates have been identified that would require dose adjustment of albiglutide. Albiglutide lowers the fasting plasma glucose and reduces postprandial glucose excursions. In addition, beta-cell secretion is enhanced by albiglutide during hyperglycemia, whereas secretion is suppressed during hypoglycemia; alpha-cell response to hypoglycemia is not impaired by albiglutide. Albiglutide does not prolong the corrected QT interval but has a modest effect on heart rate in patients with type 2 diabetes mellitus. Dose adjustment is not suggested in patients with renal impairment, but experience in patients with severe renal impairment is very limited, and it is recommended that albiglutide be used with care in such patients due to an increased frequency of diarrhea, nausea, and vomiting. No clinically relevant drug interactions have been observed in clinical trials.
Following SC administration of a single 30-mg dose to subjects with type 2 diabetes mellitus, maximum concentrations of albiglutide were reached at 3 to 5 days post-dosing. The mean peak concentration (C max) and mean area under the time-concentration curve (AUC) of albiglutide were 1.74 mcg/mL and 465 mcg.h/mL, respectively, following a single dose of 30 mg albiglutide in type 2 diabetes mellitus subjects. Steady-state exposures are achieved following 4 to 5 weeks of once-weekly administration. Exposures at the 30-mg and 50-mg dose levels were consistent with a dose-proportional increase. Similar exposure is achieved with SC administration of albiglutide in the abdomen, thigh, or upper arm. The absolute bioavailability of albiglutide following SC administration has not been evaluated. The mean estimate of apparent volume of distribution of albiglutide following SC administration is 11 L. As albiglutide is an albumin fusion molecule, plasma protein binding has not been assessed. The mean apparent clearance of albiglutide is 67 mL/hr with an elimination half-life of approximately 5 days, making albiglutide suitable for once-weekly administration.

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Biotransformation studies have not been performed. Because albiglutide is an albumin fusion protein, it likely follows a metabolic pathway similar to native human serum albumin, which is catabolized primarily in the vascular endothelium.
Albiglutide is a protein for which the expected metabolic pathway is degradation to small peptides and individual amino acids by ubiquitous proteolytic enzymes. Classical biotransformation studies have not been performed. Because albiglutide is an albumin fusion protein, it likely follows a metabolic pathway similar to native human serum albumin which is catabolized primarily in the vascular endothelium.

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4-7 days.
The elimination half-life of albiglutide following subcutaneous administration is 5 days, making the drug suitable for once-weekly administration.

In large clinical trials, serum enzyme elevations were no more common with albiglutide therapy than with placebo or comparator agents, and no instances of clinically apparent liver injury were reported. Since licensure, there have been no published case reports of hepatotoxicity due to albiglutide and the product label does not list liver injury as an adverse event. Thus, liver injury due to albiglutide must be rare, if it occurs at all.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

[1]. Expert Opin Biol Ther . 2016 Dec;16(12):1557-1569.

Albiglutide is a glucagon-like peptide-1 agonist (GLP-1) biologic drug indicated in the treatment of type 2 diabetes. It is marketed under the brands Eperzan and Tanzeum by GSK (GlaxoSmithKline). It is a dipeptidyl peptidase-4-resistant glucagon-like peptide-1 dimer fused to human albumin. Albiglutide was approved on April 15, 2014 by the FDA.
Albiglutide is a recombinant DNA produced polypeptide analogue of human glucagon-like peptide-1 (GLP-1) which is used in combination with diet and exercise in the therapy of type 2 diabetes, either alone or in combination with other antidiabetic agents. There have been no published reports of hepatotoxicity attributed to albiglutide therapy.
Albiglutide is a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, with antihyperglycemic activity. Albiglutide is composed of a GLP-1 (7-36) dimer fused to recombinant human albumin. Upon subcutaneous administration, this agent has a half-life of 4-7 days and resists degradation by dipeptidyl peptidase-4 (DPP-4).
See also: Albiglutide (annotation moved to).

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Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Eperzan is indicated for the treatment of type 2 diabetes mellitus in adults to improve glycaemic control as: MonotherapyWhen diet and exercise alone do not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate due to contraindications or intolerance. Add-on combination therapyIn combination with other glucose-lowering medicinal products including basal insulin, when these, together with diet and exercise, do not provide adequate glycaemic control (see section 4. 4 and 5. 1 for available data on different combinations).
Treatment of type II diabetes mellitus

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Albiglutide is an agonist of the GLP-1 (glucagon-like peptide 1) receptor and augments glucose-dependent insulin secretion. Albiglutide also slows gastric emptying.
Tanzeum is an agonist of the GLP-1 receptor and augments glucose-dependent insulin secretion. Tanzeum also slows gastric emptying.

C148H224N40O45

3283.6

3281.646

782500-75-8

Albiglutide fragment TFA; Albiglutide fragment; 224638-84-0

145994868

White to yellow powder

1.5±0.1 g/cm3

1.661

-5.2

1390

49

50

109

233

7620

29

O=C([C@H](CC(C)C)NC([C@H](CC1=CNC2C=CC=CC1=2)NC([C@@H](C)NC([C@H]([C@H](C)CC)NC([C@H](CC1C=CC=CC=1)NC([C@H](CCC(=O)O)NC([C@H](CCCCN)NC([C@@H](C)NC([C@@H](C)NC([C@H](CCC(N)=O)NC(CNC([C@H](CCC(=O)O)NC([C@H](CC(C)C)NC([C@H](CC1C=CC(=CC=1)O)NC([C@H](CO)NC([C@H](CO)NC([C@H](C(C)C)NC([C@H](CC(=O)O)NC([C@H](CO)NC([C@H]([C@H](C)O)NC([C@H](CC1C=CC=CC=1)NC([C@@H]([C@H](C)O)NC(CNC([C@H](CCC(=O)O)NC(CNC([C@H](CC1=CN=CN1)N)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)N[C@H](C(N[C@H](C(NCC(N[C@H](C(N)=O)CCCNC(=N)N)=O)=O)CCCCN)=O)C(C)C

JYDZPPZAYQTOIV-OTSUTHPESA-N

InChI=1S/C148H224N40O45/c1-16-76(10)119(145(231)166-79(13)125(211)174-103(59-85-62-158-90-35-24-23-34-88(85)90)135(221)176-99(55-73(4)5)136(222)185-117(74(6)7)143(229)173-92(36-25-27-51-149)127(213)160-65-109(196)167-91(122(153)208)38-29-53-157-148(154)155)187-137(223)101(56-82-30-19-17-20-31-82)177-132(218)97(46-50-115(204)205)172-131(217)93(37-26-28-52-150)170-124(210)78(12)164-123(209)77(11)165-130(216)96(43-47-108(152)195)169-111(198)66-161-129(215)95(45-49-114(202)203)171-133(219)98(54-72(2)3)175-134(220)100(58-84-39-41-87(194)42-40-84)178-140(226)105(68-189)181-142(228)107(70-191)182-144(230)118(75(8)9)186-139(225)104(61-116(206)207)179-141(227)106(69-190)183-147(233)121(81(15)193)188-138(224)102(57-83-32-21-18-22-33-83)180-146(232)120(80(14)192)184-112(199)67-162-128(214)94(44-48-113(200)201)168-110(197)64-159-126(212)89(151)60-86-63-156-71-163-86/h17-24,30-35,39-42,62-63,71-81,89,91-107,117-121,158,189-194H,16,25-29,36-38,43-61,64-70,149-151H2,1-15H3,(H2,152,195)(H2,153,208)(H,156,163)(H,159,212)(H,160,213)(H,161,215)(H,162,214)(H,164,209)(H,165,216)(H,166,231)(H,167,196)(H,168,197)(H,169,198)(H,170,210)(H,171,219)(H,172,217)(H,173,229)(H,174,211)(H,175,220)(H,176,221)(H,177,218)(H,178,226)(H,179,227)(H,180,232)(H,181,228)(H,182,230)(H,183,233)(H,184,199)(H,185,222)(H,186,225)(H,187,223)(H,188,224)(H,200,201)(H,202,203)(H,204,205)(H,206,207)(H4,154,155,157)/t76-,77-,78-,79-,80+,81+,89+,91+,92+,93+,94+,95+,96+,97+,98+,99+,100+,101+,102+,103+,104+,105+,106+,107+,117+,118+,119+,120+,121+/m1/s1

(4S)-5-[[2-[[(2S,3S)-1-[[(2S)-1-[[(2S,3S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-5-amino-1-[[(2R)-1-[[(2R)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S,3R)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[2-[[(2S)-1-amino-5-carbamimidamido-1-oxopentan-2-yl]amino]-2-oxoethyl]amino]-1-oxohexan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-2-oxoethyl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-2-oxoethyl]amino]-4-[[2-[[(2S)-2-amino-3-(1H-imidazol-5-yl)propanoyl]amino]acetyl]amino]-5-oxopentanoic acid

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)