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].

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].

---

Indinavir is a clinical inhibitor of HIV-1 protease. Its inhibition constants (Ki) were determined against wild-type HIV-1 protease (PR) and several drug-resistant mutants (PR_L24I, PR_I50V, PR_G73S). [3]
The Ki of indinavir for wild-type PR was 0.54 nM. The Ki increased to 1.40 nM (2.6-fold) for PR_L24I, 27.0 nM (50-fold) for PR_I50V, and remained similar at 0.55 nM for PR_G73S. [3]
High-resolution crystal structures (1.10–1.50 Å) of indinavir in complex with wild-type and mutant proteases (PR_L24I, PR_I50V, PR_G73S) were determined. Indinavir binds via a set of seven direct hydrogen bonds to protease residues and four water-mediated interactions. The structures reveal how mutations (especially I50V) reduce van der Waals contacts with the inhibitor, leading to increased Ki. [3]

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

The inhibition constant (Ki) for indinavir was obtained from IC₅₀ values estimated from an inhibitor dose-response curve using a spectrophotometric assay with a chromogenic substrate (K-A-R-V-Nle-p-nitroPhe-E-A-Nle-amide, a CA/p2 cleavage site analog). [3]
PR at a final concentration of 70–120 nM was added to various concentrations of substrate (25–400 μM) in 50 mM sodium acetate (pH 5.0), 0.1 M NaCl, 1 mM EDTA, 1 mM β-mercaptoethanol. Hydrolysis was monitored by the decrease in absorbance at 310 nm. [3]
The Ki values were calculated using the equation: Ki = (IC₅₀ – [E]) / (1 + [S]/K_m), where [E] and [S] are the concentrations of PR and substrate, respectively. [3]

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.

---

Lymphocyte proliferation assay: PBMCs from healthy volunteers were pre-cultured in medium alone or with different concentrations of Indinavir for 18 hours in 96-well plates. Cells were then stimulated with anti-CD3 mAb (0.5 μg/mL), PHA (2 μg/mL), Con A (2 μg/mL), PMA (10 ng/mL) plus ionomycin (1 μM), or controls for an additional 48 hours. Cultures were pulsed with [¹⁴C]-thymidine (1 μCi/well) for the last 18 hours, and incorporation was measured by scintillation counting. Results are expressed as a percentage of the response in cultures without Indinavir. [1]
Cell-cycle and apoptosis analysis in primary PBMCs: PBMCs from healthy volunteers or HIV-infected children were pre-incubated with or without different concentrations of Indinavir for 18 hours, followed by stimulation with anti-CD3 mAb (0.5 μg/mL) or control antibody for an additional 48 hours. Cells were harvested, fixed in 70% ethanol, stained with propidium iodide (50 μg/mL) and RNase A (100 μg/mL), and analyzed by flow cytometry to determine cell-cycle distribution (using multicycle software) and apoptosis (sub-G1 population). [1]
Apoptosis assay in cell lines: Jurkat and PM1 T cells were cultured with anti-Fas mAb CH11 (100 ng/mL) in the presence or absence of different concentrations of Indinavir for 2, 6, and 18 hours. In separate experiments, cells were pre-cultured with Indinavir for 18 hours before adding CH11. Apoptosis was determined by propidium iodide staining and flow cytometry. [1]
Cell-cycle analysis in cell lines: Jurkat and PM1 T cells were cultured with different concentrations of Indinavir for 24, 48, and 72 hours, stained with propidium iodide, and analyzed by flow cytometry for cell-cycle distribution. [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 of HIV-infected children aged 4–17 years who received an antiretroviral regimen consisting of oral indinavir (initial dose 500 mg/m² every 8 hours; subsequent average doses 2043 mg/m² 3 or 4 times daily), their mean peak and trough plasma concentrations were 7.3 μg/ml and 0.29 μg/ml, respectively. Indinavir is rapidly absorbed after oral administration, reaching peak concentrations in approximately 1 hour. Unlike other drugs in its class, food affects the bioavailability of indinavir; high-calorie, high-fat foods can reduce plasma concentrations by 75%. Indinavir is primarily excreted in feces, including unabsorbed drug and metabolites. Following an oral administration of 400 mg of radiolabeled indinavir, 83% of the dose was excreted in feces (19.1% unchanged) and 19% in urine (9.4% unchanged). Following a single oral administration of 700 mg or 1000 mg indinavir, 10.4% and 12% of the drug were excreted unchanged in urine, respectively. To characterize the steady-state pharmacokinetics of indinavir in cerebrospinal fluid and plasma, intensive cerebrospinal fluid sampling was performed in eight adults infected with human immunodeficiency virus (HIV) during treatment with indinavir (800 mg every 8 hours) in combination with a nucleoside reverse transcriptase inhibitor. Nine cerebrospinal fluid samples and 11 plasma samples were collected from each subject. Free indinavir accounted for 94.3% of the total drug in cerebrospinal fluid and 41.7% of the total drug in plasma. The mean peak concentration, 8-hour concentration, and area under the concentration-time curve (AUC(0-8)) of free indinavir in cerebrospinal fluid (CSF) were 294 nmol/L, 122 nmol/L, and 1616 nmol/L·hr, respectively. The AUC(0-8) ratio of free indinavir in CSF to plasma was 14.7% ± 2.6%, and was not correlated with blood-brain barrier integrity or intrathecal immune activation indicators. The concentration level of indinavir achieved in CSF should help control the replication of human immunodeficiency virus type 1 in this site. The CSF to plasma AUC(0-8) ratio suggests that other clearance mechanisms exist besides passive diffusion across the blood-brain barrier, such as P-glycoprotein-mediated efflux. For more complete data on the absorption, distribution, and excretion of indinavir sulfate (7 metabolites), please visit the HSDB record page.

---

Metabolism/Metabolites
Indinavir is metabolized to at least seven metabolites, including one glucuronide conjugate and six oxidative metabolites. The identified major metabolic pathways include glucuronidation of pyridine nitrogen, pyridine N-oxidation, para-hydroxylation of benzyl group, 3-hydroxylation of indinavir, and N-depyridine methylation. In vitro studies have shown that the cytochrome P-450 isoenzyme CYP3A4 is the major enzyme involved in the formation of oxidative metabolites.

---

Biological Half-Life
In a study of adult patients with cirrhosis and mild to moderate hepatic impairment, the elimination half-life of the drug was prolonged to 2.8 hours.
The mean plasma half-life of indinavir is 1.8 hours. In HIV-infected children aged 4–17 years receiving antiretroviral regimens including oral indinavir, the mean plasma half-life of the drug was 1.1 hours.

Effects During Pregnancy and Lactation
◉ Overview of Indinavir Use During Lactation
Indinavir has been discontinued in the United States. Limited experience has been published regarding the use of indinavir during lactation, but some infants may have higher drug concentrations in their breast milk. Indinavir use during lactation is not recommended. Achieving and maintaining viral suppression through antiretroviral therapy can reduce the risk of breast milk transmission to below 1%, but not zero. For HIV-infected individuals receiving antiretroviral therapy with a persistently low viral load, breastfeeding should be supported if they choose to do so. If viral load is not suppressed, pasteurized donor breast milk or formula is recommended.
◉ Impact on Breastfed Infants
No published information found as of the revision date.
◉ Impact on Lactation and Breast Milk
Gynecomastia has been reported in men receiving highly effective antiretroviral therapy. Gynecomastia is initially unilateral, but about half of cases develop into bilateral gynecomastia. No changes in serum prolactin levels were observed, and these typically resolve spontaneously within one year even with continued treatment. Some case reports and in vitro studies suggest that protease inhibitors may cause hyperprolactinemia and galactorrhea in some male patients, but this remains controversial. The implications of these findings for lactating mothers are unclear. For mothers who have established lactation, prolactin levels may not affect their ability to breastfeed.

---

Drug Interactions
Cytochrome P450 CYP3A4 substrates astemizole, cisapride, midazolam, terfenadine, and triazolam have not been studied; because indinavir competes with CYP3A4, it may lead to inhibition of the metabolism of these drugs, resulting in elevated plasma concentrations and thus a risk of serious and/or life-threatening side effects; concomitant use of indinavir with any of the above drugs is not recommended.
Concomitant administration of cimetidine and indinavir does not affect the area under the plasma concentration-time curve (AUC) of indinavir.
Ampravir interferes with the metabolism of rifabutin and significantly increases its serum concentration; it is recommended to reduce the rifabutin dose to at least half of the recommended dose. Rifabutin can reduce the AUC of ampravir by 15%; if rifabutin is taken concurrently with ampravir, patients should be monitored for neutropenia weekly and as clinically necessary.
Concomitant use with clarithromycin results in a 29% increase in the AUC of indinavir and a 53% increase in the AUC of clarithromycin; no dose adjustment is required.
For more complete data on interactions of indinavir sulfate (18 in total), please visit the HSDB record page.

---

Non-human toxicity values
Canine intraperitoneal LD50 > 640 mg/kg
Canine oral LD50 > 640 mg/kg
Mouse intraperitoneal LD50 > 5 g/kg
Mouse oral LD50 > 5 g/kg
For more complete non-human toxicity data for indinavir sulfate (6 types in 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
Indinavir is an HIV protease inhibitor. Indinavir, when used in combination with antiretroviral drugs, is indicated for the treatment of HIV infection. /US product label contains/

---

Drug Warnings Approximately 9% of adult patients treated with indinavir have reported developing kidney/urinary tract stones, which may present as back pain, with or without hematuria (including microscopic hematuria). The incidence in children is 29%. The most common adverse reactions to indinavir treatment involve the gastrointestinal tract. In treatment-nausea-infected HIV-infected adults receiving indinavir monotherapy, the incidence of abdominal pain, nausea, vomiting, and diarrhea was 16.6%, 11.7%, 8.4%, and 3.3%, respectively; the incidence of acid reflux, anorexia, dyspepsia, increased appetite, and dysgeusia was 1.5% to 2.7%. In the 028 study, among patients receiving indinavir in combination with zidovudine, the incidence of abdominal pain, nausea, vomiting, and diarrhea was 16%, 31.9%, 17.8%, and 3%, respectively; the incidence of acid reflux, anorexia, dyspepsia, increased appetite, and dysgeusia ranged from 1.5% to 8.4%. The safety and efficacy of indinavir in pediatric patients have not been established. Indinavir has been used in a small number of HIV-infected children aged 3 months and older without adverse events. However, the incidence of kidney/urinary tract stones in pediatric patients treated with indinavir (29%) was higher than in adult patients treated with the drug (9.2%). In clinical studies, approximately 14% of patients treated with indinavir developed asymptomatic hyperbilirubinemia (i.e., total serum bilirubin concentration exceeding 2.5 mg/dL). Asymptomatic bilirubinemia typically presents as elevated indirect bilirubin, while elevated serum AST (SGOT) or ALT (SGPT) levels are rare (i.e., occurring in less than 1% of patients treated with this drug). Acute hepatitis has been reported in a small number of patients receiving indinavir in combination with other drugs, sometimes leading to liver failure and death. Jaundice occurs in 1.5% to 2.1% of patients treated with indinavir. For more complete data on drug warnings for indinavir sulfate (21 in total), please visit the HSDB record page. Indinavir is one of the earliest HIV-1 protease inhibitors used clinically. High levels of resistance to indinavir are associated with substitutions of up to 11 protease residues (in different combinations). [3] This study analyzed the molecular basis of drug resistance by comparing the crystal structure, dimer stability, and kinetics of wild-type HIV-1 protease and drug-resistant mutants (L24I, I50V, G73S) with indinavir complexes. [3] The I50V mutation located on the flexible valve that interacts with the inhibitor resulted in a significant 50-fold increase in the Ki value of indinavir, mainly due to the weakening of the van der Waals interaction between Val50 and the inhibitor. [3] The L24I mutation located near the catalytic site Asp25 had a smaller effect on the Ki value (an increase of 2.6-fold), but reduced catalytic activity and dimer stability. [3] The distal mutation G73S, located far from the active site, had little effect on the inhibitory effect of indinavir, but changed the substrate specificity by forming a new hydrogen bond network, which can transmit the 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

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

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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 )

Solubility in Formulation 1: ≥ 2.5 mg/mL (3.51 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

---

Solubility in Formulation 2: ≥ 2.5 mg/mL (3.51 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
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.

---

View More

Solubility in Formulation 3: ≥ 2.5 mg/mL (3.51 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

Solubility in Formulation 4: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.5 mg/mL (3.51 mM)

---

Solubility in Formulation 5: 100 mg/mL (140.48 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

---

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