MMP-2;HIV-1
Indinavir sulfate (0-50 μM; 18 h) inhibits the G0/G1 phase of the lymphocyte cell cycle in PBMCs and reduces the ability of the cells to proliferate lymphomegaly[1].
In vitro, indinavir sulfate (40 μM–40 nM; 5 days) inhibits Huh7 and SK-HEP-1 hepatocarcinoma cells' ability to invade cells and activate MMPs-2 (40 μM–40 nM; 48 h)[2].

硫酸茚地那韦（0-50 μM；18 小时）抑制 PBMC 中淋巴细胞细胞周期的 G0/G1 期，降低细胞增殖淋巴肿大的能力[1]。
在体外，硫酸茚地那韦（40 μM– 40 nM；5 天）抑制 Huh7 和 SK-HEP-1 肝癌细胞侵袭细胞并激活 MMPs-2 的能力（40 μM–40 nM；48 小时）[2]。

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Indinavir是HIV-1蛋白酶的临床抑制剂。本研究测定了其对野生型HIV-1蛋白酶（PR）及几种耐药突变体（PR_L24I, PR_I50V, PR_G73S）的抑制常数（Ki）。[3]
Indinavir对野生型PR的Ki为0.54 nM。对PR_L24I的Ki增至1.40 nM（2.6倍），对PR_I50V的Ki大幅增至27.0 nM（50倍），而对PR_G73S的Ki基本保持不变，为0.55 nM。[3]
研究解析了Indinavir与野生型及突变蛋白酶（PR_L24I, PR_I50V, PR_G73S）复合物的高分辨率晶体结构（1.10–1.50 Å）。Indinavir通过7个直接氢键和4个水分子介导的相互作用与蛋白酶结合。结构揭示了突变（尤其是I50V）如何减少与抑制剂之间的范德华作用力，从而导致Ki值升高。[3]

硫酸茚地那韦（70 mg/kg；ig；每天一次，持续 3 周）可抑制体内肝癌细胞的生长[2]。

通过使用显色底物（K-A-R-V-Nle-p-nitroPhe-E-A-Nle-amide，一种CA/p2切割位点类似物）的分光光度法测定抑制剂量反应曲线，从中估算IC₅₀值，进而获得Indinavir的抑制常数（Ki）。[3]
将终浓度为70–120 nM的PR加入到含有不同浓度底物（25–400 μM）的50 mM醋酸钠（pH 5.0）、0.1 M NaCl、1 mM EDTA、1 mM β-巯基乙醇的缓冲液中。通过监测310 nm波长处吸光度的降低来跟踪水解反应。[3]
使用公式 Ki = (IC₅₀ – [E]) / (1 + [S]/K_m) 计算Ki值，其中[E]和[S]分别是PR和底物的浓度。[3]

细胞系：PBMC（来自健康和感染 HIV 的志愿者）
浓度：0-50 µM
孵育时间：18 小时（预处理；用抗 CD3 刺激另外 48 小时）
结果：封闭抗CD3以剂量依赖性方式诱导细胞周期进程。导致淋巴细胞增殖反应的剂量依赖性减少。

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淋巴细胞增殖实验： 健康志愿者的PBMCs在96孔板中单独使用培养基或与不同浓度的Indinavir预培养18小时。然后用抗CD3 mAb (0.5 μg/mL)、PHA (2 μg/mL)、Con A (2 μg/mL)、PMA (10 ng/mL) 加离子霉素 (1 μM) 或对照物刺激细胞，再培养48小时。在最后18小时加入[¹⁴C]-胸腺嘧啶 (1 μCi/孔)，通过闪烁计数法测量掺入量。结果以未经Indinavir处理的培养物的响应百分比表示。[1]
原代PBMCs的细胞周期和凋亡分析： 将健康志愿者或HIV感染儿童的PBMCs与或不与不同浓度的Indinavir预孵育18小时，然后用抗CD3 mAb (0.5 μg/mL) 或对照抗体刺激，再培养48小时。收集细胞，用70%乙醇固定，用碘化丙啶 (50 μg/mL) 和RNase A (100 μg/mL) 染色，并通过流式细胞术分析细胞周期分布（使用多周期软件）和凋亡（亚G1群体）。[1]
细胞系凋亡实验： 将Jurkat和PM1 T细胞与抗Fas mAb CH11 (100 ng/mL) 在不同浓度的Indinavir存在或不存在下培养2、6和18小时。在单独的实验中，细胞在添加CH11前先用Indinavir预培养18小时。通过碘化丙啶染色和流式细胞术测定细胞凋亡。[1]
细胞系细胞周期分析： 将Jurkat和PM1 T细胞与不同浓度的Indinavir培养24、48和72小时，用碘化丙啶染色，并通过流式细胞术分析细胞周期分布。[1]

Animal Model: Nude mice(s.c. into Huh7 and SK-HEP-1 cells)[2].
Dosage: 70 mg/kg
Administration: Oral gavage; once a day for 3 weeks.
Result: Delaied the growth of s.c. implanted hepatocarcinoma xenografts in nude mice compared with placebo.

Absorption, Distribution and Excretion
In a study in HIV-infected children 4-17 years of age receiving an antiretroviral regimen that included oral indinavir (initial dosage of 500 mg/sq m every 8 hours; subsequent dosage averaging 2043 mg/sq m daily in 3 or 4 doses); peak and trough plasma concentrations averaging 7.3 and 0.29 ug/ml, respectively.
Indinavir is rapidly absorbed after oral administration, with peak levels achieved in approximately 1 hour. Unlike other drugs in this class, food can adversely affect indinavir bioavailability; a high-calorie, high-fat meal reduces plasma concentrations by 75%.
Indinavir is excreted principally in the feces, both as unabsorbed drug and metabolites. Following oral administration of 400 mg of radiolabeled indinavir, 83% of the dose is recovered in feces (19.1% as unchanged drug) and 19% is recovered in urine (9.4% as unchanged drug). Following oral administration of a single 700- or 1000-mg dose of indinavir, 10.4 or 12%, respectively, is excreted unchanged in urine.
To characterize steady-state indinavir pharmacokinetics in cerebrospinal fluid and plasma, 8 adults infected with human immunodeficiency virus underwent intensive cerebrospinal fluid sampling while receiving indinavir (800 mg every 8 hours) plus nucleoside reverse transcriptase inhibitors. Nine and 11 serial cerebrospinal fluid and plasma samples, respectively, were obtained from each subject. Free indinavir accounted for 94.3% of the drug in cerebrospinal fluid and 41.7% in plasma. Mean values of cerebrospinal fluid peak concentration, concentration at 8 hours, and area under the concentration-time profile calculated over the interval 0 to 8 hours (AUC(0-8)) for free indinavir were 294 nmol/L, 122 nmol/L, and 1616 nmol/L x hr, respectively. The cerebrospinal fluid-to-plasma AUC(0-8) ratio for free indinavir was 14.7% +/- 2.6% and did not correlate with indexes of blood-brain barrier integrity or intrathecal immune activation. Indinavir achieves levels in cerebrospinal fluid that should contribute to control of human immunodeficiency virus type 1 replication in this compartment. The cerebrospinal fluid-to-plasma AUC (0-8) ratio suggests clearance mechanisms in addition to passive diffusion across the blood-cerebrospinal fluid barrier, perhaps by P-glycoprotein-mediated efflux.
For more Absorption, Distribution and Excretion (Complete) data for INDINAVIR SULFATE (7 total), please visit the HSDB record page.

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Metabolism / Metabolites
Indinavir is metabolized to at least 7 metabolites including 1 glucuronide conjugate and 6 oxidative metabolites. Major metabolic pathways identified include glucuronidation at the pyridine nitrogen, pyridine N-oxidation, para-hydroxylation of the phenylmethyl group, 3-hydroxylation of the indan, and N-depyridomethylation. In vitro studies indicate that cytochrome P-450 isoenzyme CYP3A4 is the major enzyme involved in the formation of the oxidative metabolites.

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Biological Half-Life
In a study in adults with cirrhosis and mild to moderate hepatic impairment, the elimination half-life of the drug was prolonged to 2.8 hours.
The plasma half-life of indinavir averages 1.8 hours. In HIV-infected children 4-17 years of age receiving an antiretroviral regimen that included oral indinavir, plasma half-life of the drug averaged 1.1 hours.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Indinavir is no longer marketed in the US. Published experience with indinavir during breastfeeding is limited, but some infants may achieve high levels of the drug in breastmilk. Indinavir is not a recommended agent during breastfeeding. Achieving and maintaining viral suppression with antiretroviral therapy decreases breastfeeding transmission risk to less than 1%, but not zero. Individuals with HIV who are on antiretroviral therapy with a sustained undetectable viral load and who choose to breastfeed should be supported in this decision. If a viral load is not suppressed, banked pasteurized donor milk or formula is recommended.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Gynecomastia has been reported among men receiving highly active antiretroviral therapy. Gynecomastia is unilateral initially, but progresses to bilateral in about half of cases. No alterations in serum prolactin were noted and spontaneous resolution usually occurred within one year, even with continuation of the regimen. Some case reports and in vitro studies have suggested that protease inhibitors might cause hyperprolactinemia and galactorrhea in some male patients, although this has been disputed. The relevance of these findings to nursing mothers is not known. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

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Interactions
Studies have not been done with the cytochrome p450 CYP3A4 substrates astemizole, cisapride, midazolam, terfenadine, and triazolam; because competition for CYP3A4 by indinavir could result in inhibition of the metabolism of these medications and elevated plasma concentrations, there is a potential for serious and/or life-threatening side effects; concurrent use of indinavir with any of these medications is not recommended.
Concurrent administration /of cimetidine and indinavir/ does not affect the area under the plasma concentration-time curve (AUC) of indinavir.
Amprenavir interferes with the metabolism of rifabutin and significantly increases rifubutin serum concentrations; it is recommended that the dose of rifabutin be reduced by at least half of the recommended dose; rifabutin decreases the AUC of amprenavir by 15%; patients should be monitored for neutropenia once a week and as clinically indicated if rifabutin is given concurrently with amprenavir.
Concurrent use /with clarithromycin/ results in a 29% increase in the AUC of indinavir and a 53% increase in the AUC of clarithromycin; dosing modification is not required.
For more Interactions (Complete) data for INDINAVIR SULFATE (18 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Dog Intraperitoneal > 640 mg/kg
LD50 Dog oral > 640 mg/kg
LD50 Mouse Intraperitoneal > 5 g/kg
LD50 Mouse oral > 5 g/kg
For more Non-Human Toxicity Values (Complete) data for INDINAVIR SULFATE (6 total), please visit the HSDB record page.

[1]. The HIV protease inhibitor Indinavir inhibits cell-cycle progression in vitro in lymphocytes of HIV-infected and uninfected individuals. Blood. 2001 Jul 15;98(2):383-9.

[2]. Evaluation of antitumoral properties of the protease inhibitor indinavir in a murine model of hepatocarcinoma. Clin Cancer Res. 2006 Apr 15;12(8):2634-9.

[3]. Kinetic, stability, and structural changes in high-resolution crystal structures of HIV-1 protease with drug-resistant mutations L24I, I50V, and G73S. J Mol Biol. 2005 Dec 9;354(4):789-800.

[4]. A search for medications to treat COVID-19 via in silico molecular docking models of the SARS-CoV-2 spike glycoprotein and 3CL protease. Travel Med Infect Dis. 2020 May-Jun;35:101646.

[5]. AIDS.1996 May;10(5):485-92.

[6]. J Mol Biol.2005 Dec 9;354(4):789-800.

Therapeutic Uses
HIV Protease Inhibitors.
Indinavir with antiretroviral agents is indicated for the treatment of HIV infection. /Included in US product labeling/

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Drug Warnings
Nephrolithiasis/urolithiasis, which may present as flank pain with or without hematuria (including microscopic hematuria), has been reported in about 9% of adults and 29% of pediatric patients receiving indinavir.
The most frequent adverse effects associated with indinavir therapy involve the GI tract. ...In treatment-naive HIV-infected adults, abdominal pain, nausea, vomiting, and diarrhea occurred in 16.6, 11.7, 8.4, and 3.3%, respectively, and acid regurgitation, anorexia, dyspepsia, increased appetite, and taste perversion occurred in 1.5-2.7% of patients receiving indinavir monotherapy. In patients in study 028 receiving indinavir in conjunction with zidovudine, abdominal pain, nausea, vomiting, and diarrhea occurred in 16, 31.9, 17.8, and 3%, respectively, and acid regurgitation, anorexia, dyspepsia, increased appetite, and taste perversion occurred in 1.5-8.4% of patients. ...Safety and efficacy of indinavir in pediatric patients have not been established. Indinavir has been used in a limited number of HIV-infected children 3 months of age or older without unusual adverse effects. However, nephrolithiasis/urolithiasis has been reported more frequently in pediatric patients receiving indinavir (29%) than in adults receiving the drug (9.2%).
Asymptomatic hyperbilirubinemia (i.e., total serum bilirubin concentrations exceeding 2.5 mg/dL) has occurred in about 14% of patients receiving indinavir in clinical studies. Asymptomatic bilirubinemia usually has been reported as elevated indirect bilirubin and has been associated with increased serum AST (SGOT) or ALT (SGPT) concentrations only rarely (i.e., in less than 1% of patients receiving the drug).
Acute hepatitis sometimes resulting in hepatic failure and death have been reported in a few patients receiving indinavir in conjunction with other drugs. ...Jaundice was reported in 1.5-2.1% of patients receiving indinavir.
For more Drug Warnings (Complete) data for INDINAVIR SULFATE (21 total), please visit the HSDB record page.

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Indinavir was one of the first HIV-1 protease inhibitors in clinical use. High-level resistance to indinavir is associated with substitutions of up to 11 protease residues in different combinations. [3]
The study analyzed the molecular basis of drug resistance by comparing crystal structures, dimer stability, and kinetics of wild-type HIV-1 protease and resistant mutants (L24I, I50V, G73S) in complex with indinavir. [3]
The mutation I50V, located in the flexible flap that interacts with the inhibitor, caused a dramatic 50-fold increase in Ki for indinavir, primarily due to reduced van der Waals interactions between Val50 and the inhibitor. [3]
The mutation L24I, adjacent to catalytic Asp25, had a smaller effect on Ki (2.6-fold increase) but reduced catalytic activity and dimer stability. [3]
The distal mutation G73S, far from the active site, had minimal effect on indinavir inhibition but altered substrate specificity by forming new hydrogen bond networks that can transmit changes to the substrate-binding site. [3]

C36H49N5O8S

711.87

711.33

C, 60.74; H, 6.94; N, 9.84; O, 17.98; S, 4.50

157810-81-6

Indinavir;150378-17-9;Indinavir sulfate ethanolate;2563866-80-6

5462355

White to off-white solid powder

877.9ºC at 760 mmHg

150-153ºC

484.7ºC

5.56E-33mmHg at 25°C

3.952

201.01

6

11

12

50

1030

5

O=C([C@@H](C[C@H](O)CN(CCN(CC1=CN=CC=C1)C2)[C@@H]2C(NC(C)(C)C)=O)CC3=CC=CC=C3)N[C@H]4C(C=CC=C5)=C5C[C@H]4O.O=S(O)(O)=O

NUBQKPWHXMGDLP-BDEHJDMKSA-N

InChI=1S/C36H47N5O4.H2O4S/c1-36(2,3)39-35(45)31-24-40(22-26-12-9-15-37-21-26)16-17-41(31)23-29(42)19-28(18-25-10-5-4-6-11-25)34(44)38-33-30-14-8-7-13-27(30)20-32(33)43;1-5(2,3)4/h4-15,21,28-29,31-33,42-43H,16-20,22-24H2,1-3H3,(H,38,44)(H,39,45);(H2,1,2,3,4)/t28-,29+,31+,32-,33+;/m1./s1

(2S)-1-[(2S,4R)-4-benzyl-2-hydroxy-5-[[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino]-5-oxopentyl]-N-tert-butyl-4-(pyridin-3-ylmethyl)piperazine-2-carboxamide sulfate

trade name: Crixivan; DRG-0233; DRG0233; L-735 524 sulfate; DRG 0233; MK-639 sulfate; L 735 524; MK 639; L735 524; MK639;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

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

DMSO : ~100 mg/mL ( ~140.47 mM )
H2O :~50 mg/mL (~70.24 mM )

配方 1 中的溶解度: ≥ 2.5 mg/mL (3.51 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (3.51 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (3.51 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.5 mg/mL (3.51 mM)

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配方 5 中的溶解度: 100 mg/mL (140.48 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶.

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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。