HIV-1
MMP-2

Indinavir (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 [1].
Huh7 and SK-HEP-1 hepatocarcinoma cells' cell invasion and MMPs-2 activation are inhibited in vitro by indinavir (40 µM–40 nM; 5 days) and 40 µM–40 nM (48 h) respectively[2].

Indinavir (70 mg/kg; i.g.; once a day for 3 weeks) inhibits the growth of hepatocarcinoma cells in vivo[2].

Cell Line: PBMCs (from healthy and HIV-infected volunteers)
Concentration: 0-50 µM
Incubation Time: 18 h (pretreatment; stimulation with anti-CD3 for an additional 48 hours)
Result: Blocked anti-CD3-induced cell-cycle progression in a dose-dependent manner. Resulted in dose-dependent reduction of lymphoproliferative responses.

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: Compared to placebo, delayed the growth of s.c. implanted hepatocarcinoma xenografts in naked mice.

Absorption, Distribution and Excretion
Rapidly absorbed
Less than 20% of indinavir is excreted unchanged in the urine.

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Metabolism / Metabolites
Hepatic. Seven metabolites have been identified, one glucuronide conjugate and six oxidative metabolites. In vitro studies indicate that cytochrome P-450 3A4 (CYP3A4) is the major enzyme responsible for formation of the oxidative metabolites.
Indinavir has known human metabolites that include 1-[4-benzyl-2-hydroxy-5-[(2-hydroxy-2,3-dihydro-1H-inden-1-yl)amino]-5-oxopentyl]-N-tert-butyl-4-[(1-oxidopyridin-1-ium-3-yl)methyl]piperazine-2-carboxamide, N-tert-butyl-1-[2-hydroxy-5-[(2-hydroxy-2,3-dihydro-1H-inden-1-yl)amino]-4-[(4-hydroxyphenyl)methyl]-5-oxopentyl]-4-(pyridin-3-ylmethyl)piperazine-2-carboxamide, 1-[4-Benzyl-2-hydroxy-5-[(2-hydroxy-2,3-dihydro-1H-inden-1-yl)amino]-5-oxopentyl]-N-tert-butylpiperazine-2-carboxamide, and 1-[4-benzyl-5-[(2,3-dihydroxy-2,3-dihydro-1H-inden-1-yl)amino]-2-hydroxy-5-oxopentyl]-N-tert-butyl-4-(pyridin-3-ylmethyl)piperazine-2-carboxamide.

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Biological Half-Life
1.8 (± 0.4) hours

Hepatotoxicity
Some degree of serum aminotransferase elevations occur in a high proportion of patients taking indinavir containing antiretroviral regimens. Moderate-to severe elevations in serum aminotransferase levels (>5 times the upper limit of normal) are found in 3% to 10% of patients, although rates may be higher in patients with HIV-HCV coinfection. These elevations are usually asymptomatic and self-limited and can resolve even with continuation of the medication. Indinavir therapy also causes increases in unconjugated (indirect) and total serum bilirubin that can manifest as jaundice in up to 10% of patients. These elevations are due to the inhibition of UDP glucuronyl transferase, the hepatic enzyme responsible for conjugation of bilirubin that is deficient in Gilbert syndrome. The hyperbilirubinemia is usually mild, the increases averaging 0.3-0.5 mg/dL, but can be more marked in patients with Gilbert syndrome with increases of 1.5 mg/dL or more and clinical jaundice. The jaundice, however, is not indicative of hepatic injury. Clinically apparent acute liver injury due to indinavir is rare. The few cases that have been reported have arisen after 1 to 8 weeks of starting indinavir, and the pattern of serum enzyme elevations has varied from hepatocellular to cholestatic. Signs of hypersensitivity (fever, rash, eosinophilia) are rare as is autoantibody formation. The acute liver injury due to indinavir is usually self-limited, but it can be severe, and isolated cases of acute liver failure have been reported. In addition, initiation of indinavir based highly active antiretroviral therapy can lead to exacerbation of an underlying chronic hepatitis B or C in coinfected individuals, typically arising 2 to 12 months after starting therapy and associated with a hepatocellular pattern of serum enzyme elevations and increases in serum levels of hepatitis B virus (HBV) DNA or hepatitis C virus (HCV) RNA. Indinavir therapy has not been clearly linked to lactic acidosis and acute fatty liver that is reported in association with several nucleoside analogue reverse transcriptase inhibitors.
Likelihood score: C (frequent cause of serum bilirubin elevations and probable cause of rare instances of clinically apparent liver injury).

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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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Protein Binding
60%

[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.

Indinavir is a N-(2-hydroxyethyl)piperazine, a piperazinecarboxamide and a dicarboxylic acid diamide. It has a role as a HIV protease inhibitor.
Indinavir anhydrous is a Protease Inhibitor. The mechanism of action of indinavir anhydrous is as a HIV Protease Inhibitor, and Cytochrome P450 3A4 Inhibitor.
Indinavir is an antiretroviral protease inhibitor used in the therapy and prevention of human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS). Indinavir can cause transient and usually asymptomatic elevations in serum aminotransferase levels and mild elevations in indirect bilirubin concentration. Indinavir is a rare cause of clinically apparent, acute liver injury. In HBV or HCV coinfected patients, antiretroviral therapy with indinavir may result in an exacerbation of the underlying chronic hepatitis B or C.
Indinavir has been reported in Streptomyces with data available.
Indinavir is a synthetic hydroxyaminopentane amide agent that selectively inhibits the protease of both human immunodeficiency virus 1 and 2. The incorporation of a basic amine into the hydroxyethylene backbone improves its aqueous solubility and its oral bioavailability.
Indinavir Anhydrous is an anhydrous formulation of indinavir, a synthetic hydroxyaminopentane amide agent that selectively inhibits the protease of both human immunodeficiency virus 1 and 2. The incorporation of a basic amine into the hydroxyethylene backbone improves its aqueous solubility and its oral bioavailability.
A potent and specific HIV protease inhibitor that appears to have good oral bioavailability.

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Drug Indication
Indinavir is an antiretroviral drug for the treatment of HIV infection.
FDA Label
Crixivan is indicated in combination with antiretroviral nucleoside analogues for the treatment of HIV-1 infected adults. ,

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Mechanism of Action
Indinavir inhibits the HIV viral protease enzyme which prevents cleavage of the gag-pol polyprotein, resulting in noninfectious, immature viral particles.

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Pharmacodynamics
Indinavir is a protease inhibitor with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Protease inhibitors block the part of HIV called protease. HIV-1 protease is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV-1. Indinavir binds to the protease active site and inhibits the activity of the enzyme. This inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature non-infectious viral particles. Protease inhibitors are almost always used in combination with at least two other anti-HIV drugs.

C36H47N5O4

613.79

613.362

C, 70.45; H, 7.72; N, 11.41; O, 10.43

150378-17-9

Indinavir sulfate;157810-81-6;Indinavir sulfate ethanolate;2563866-80-6;Indinavir-d6;185897-02-3

5362440

Solid powder

1.2±0.1 g/cm3

831.6±75.0 °C at 760 mmHg

150-153ºC

456.8±37.1 °C

0.0±3.2 mmHg at 25°C

1.629

4.04

4

7

12

45

952

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

CBVCZFGXHXORBI-PXQQMZJSSA-N

InChI=1S/C36H47N5O4/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/h4-15,21,28-29,31-33,42-43H,16-20,22-24H2,1-3H3,(H,38,44)(H,39,45)/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

trade name: Crixivan; DRG-0233; L-735 524; DRG0233; MK-639; L 735 524; MK 639; DRG 233; 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

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

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)