Saquinavir is a protease inhibitor. Proteases are enzymes that break protein molecules into smaller fragments. HIV protease is crucial for intracellular viral replication and the release of mature viral particles from infected cells. Saquinavir binds to the active site of the viral protease and blocks cleavage of the viral polyprotein, hence preventing viral maturation. Saquinavir inhibits both HIV-1 and HIV-2 proteases. Research has also looked at saquinavir as a promising anti-cancer medication.

Absorption, Distribution and Excretion
The absolute bioavailability of orally administered saquinavir is only ~4%, thought to be a consequence of incomplete absorption and extensive first-pass metabolism. It is co-administered with ritonavir, another protease inhibitor and a potent inhibitor of the enzymes responsible for saquinavir's first-pass metabolism, in order to dramatically boost its serum concentrations and, by extension, its therapeutic efficacy. Following administration of saquinavir 1000mg twice daily with ritonavir 100mg twice daily the AUC24h at steady-state was 39026 ng.h/mL.
The primary means of elimination of saquinavir appears to be extensive hepatic metabolism followed by fecal excretion of both the parent drug and metabolic products. Following the administration of radiolabeled saquinavir (both orally and intravenously), approximately 81-88% of radioactivity is recovered in the feces within 5 days of dosing while only 1-3% is recovered in the urine. Mass balance studies indicate that only 13% of orally-administered plasma radioactivity is attributed to unchanged parent drug, with the remainder comprising metabolic products of saquinavir's hepatic metabolism. In contrast, intravenous administration resulted in approximately 66% of the circulating plasma radioactivity being attributed to unchanged parent drug, suggesting a high degree of first-pass metabolism with oral administration.
The steady-state volume of distribution of saquinavir is approximately 700 L, suggesting extensive distribution into tissues.
The systemic clearance of saquinavir is approximately 1.14 L/h/kg following intravenous administration.
Following administration of saquinavir in a dosage of 1200 mg 3 times daily as liquid-filled capsules, mean steady-state AUC at 3 weeks was 7249 ngh/mL compared with an AUC of 866 ngh/mL reported following administration of saquinavir hard gelatin capsules in a dosage of 600 mg 3 times daily. While the AUC of saquinavir in adults receiving liquid-filled capsules was lower at week 61-69 compared with the AUC at week 3, the AUC at week 61-69 was greater than the AUC at the same time point in HIV-infected adults receiving saquinavir as hard gelatin capsules (600 mg 3 times daily).
The relative oral bioavailability of saquinavir from liquid-filled (soft gelatin) capsules is estimated to average 331% (range: 207-530%) of that achieved with hard gelatin capsules of the drug when single 600-mg doses are administered. This would represent a calculated average oral bioavailability from the liquid-filled capsules of about 13% based on an average absolute bioavailability of 4% from the hard capsules; however, these are calculated estimates and not based on actual determination of absolute oral bioavailability from the liquid-filled capsules.
Saquinavir and its metabolites are eliminated from the body primarily through the biliary system and feces (more than 95% of the drug), with minimal urinary excretion (less than 3% of administered drug).
Oral bioavailability of the hard-gelatin capsule formulation of saquinavir (saquinavir mesylate, invirase) is only 4% due to limited absorption and extensive first-pass metabolism, with considerable interpatient variability. ... Absorption of saquinavir may be enhanced when the drug is taken with a high-calorie, high-fat meal. In addition, saquinavir demonstrates a greater than dose-proportional increase in exposure. For example, tripling the oral dose of saquinavir is associated with an eightfold increase in exposure.
For more Absorption, Distribution and Excretion (Complete) data for SAQUINAVIR (10 total), please visit the HSDB record page.

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Metabolism / Metabolites
Saquinavir is extensively metabolized in the liver following oral administration, and _in vitro_ studies have shown that >90% of its biotransformation is mediated by the CYP3A4 isoenzyme. Saquinavir is rapidly metabolized to a number of inactive mono- and di-hydroxylated compounds.
Results of in vitro studies indicate that saquinavir is rapidly metabolized in the liver to several monohydroxylated and dihydroxylated inactive metabolites. Metabolism of saquinavir is mediated by cytochrome P450; the isoenzyme CYP3A4 is involved in more than 90% of this metabolism. Orally administered saquinavir appears to undergo substantial metabolism on first pass through the liver.
Saquinavir is metabolized primarily by hepatic CYP3A4. The metabolites of saquinavir are not active against HIV-1.
Saquinavir has known human metabolites that include (2S)-N-[(2S,3R)-4-[(3S,4aS,8aS)-3-(tert-butylcarbamoyl)-7-hydroxy-decahydroisoquinolin-2-yl]-3-hydroxy-1-phenylbutan-2-yl]-2-[(quinolin-2-yl)formamido]butanediamide, (2S)-N-[(2S,3R)-4-[(3S,4aS,8aS)-3-[(1-hydroxy-2-methylpropan-2-yl)carbamoyl]-decahydroisoquinolin-2-yl]-3-hydroxy-1-phenylbutan-2-yl]-2-[(quinolin-2-yl)formamido]butanediamide, and (2S)-N-[(2S,3R)-4-[(3S,4aR,8aS)-3-(tert-butylcarbamoyl)-6-hydroxy-decahydroisoquinolin-2-yl]-3-hydroxy-1-phenylbutan-2-yl]-2-[(quinolin-2-yl)formamido]butanediamide.

Interactions
Concurrent use of saquinavir with terfenadine has resulted in an increase in the plasma concentrations of terfenadine; competition for the cytochrome p450 enzyme CYP3A by saquinavir may also inhibit the metabolism of astemizole, cisapride, ergot derivatives, midazolam, or triazolam, due to the potential for serious and/or life-threatening cardiac arrhythmias or prolonged sedation, concurrent use of any of these medications with saquinavir mesylate capsules or saquinavir soft gelatin capsules is not recommended.
Concurrent administration of saquinavir mesylate capsules with these medications /calcium channel blocking agents, clindamycin, dapsone, or quinidine/ which are substrates of the CYP3A4 isoenzyme of the cytochrome p450 enzyme system, may result in elevated plasma concentrations of these medications; patients should be monitored for toxicities associated with these medications.
Ethanol-intake decreases the bioavailability of SQV /saquinavir/ after oral administration alone or with RTV /ritonavir/.
Concurrent administration of rifabutin or rifampin with saquinavir mesylate capsules has resulted in a decrease in the steady-state AUC and peak plasma concentration of saquinavir by approximately 80% and 40%, respectively; carbamazepine, dexamethasone, phenobarbital, phenytoin, or other medications that induce CYP3A4 may also reduce saquinavir plasma concentrations; use of alternative medications should be considered if patients are taking either formulation of saquinavir.
For more Interactions (Complete) data for SAQUINAVIR (17 total), please visit the HSDB record page.

[1]. In vitro and in vivo anticancer action of Saquinavir-NO, a novel nitric oxide-derivative of the protease inhibitor saquinavir, on hormone resistant prostate cancer cells. Cell cycle. 2011, 1.

[2]. Gemini: A Noninferiority Study of Saquinavir/Ritonavir Versus Lopinavir/Ritonavir as Initial HIV-1 Therapy in Adults. JAIDS Journal of Acquired Immune Deficiency Syndromes. 2009,50 (4) :367-374.

[3]. Saquinavir.

[4]. Ritonavir or saquinavir impairs the invasion of cervical intraepithelial neoplasia cells via a reduction of MMP expression and activity. AIDS. 2012, 26 (8): 909-919.

[5]. Saquinavir Inhibits Early Events Associated with Establishment of HIV-1 Infection: Potential Role for Protease Inhibitors in Prevention. Antimicrob. Agents Chemother. 2012, 56 (8): 4381-4390.

[6]. Bardoxolone and bardoxolone methyl, two Nrf2 activators in clinical trials, inhibit SARS-CoV-2 replication and its 3C-like protease. Signal Transduct Target Ther. 2021 May 29;6(1):212.

Therapeutic Uses
Saquinavir, in combination with other antiretroviral agents, is indicated in the treatment of HIV infection or AIDS. Saquinavir soft gelatin capsule (Fortovase) is the preferred dosage form, according to the FDA. /Included in US product labeling/
Saquinavir was not detected in cord blood. Saquinavir soft-gel capsules are well tolerated during pregnancy and are not associated in this small study with birth abnormalities. Transmission of HIV infection from mother to child was successfully prevented in all cases. Low maternal exposures of saquinavir were noted. However, these did not appear to affect virologic efficacy of the combination. Samples from cord blood indicate minimal fetal exposure to saquinavir.

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Drug Warnings
The principal adverse effects associated with saquinavir therapy involve the GI tract. In adults with HIV infection receiving saquinavir liquid-filled or hard gelatin capsules in conjunction with other antiretroviral agents (e.g., 2 dideoxynucleoside reverse transcriptase inhibitors), diarrhea occurred in 15.6-19.9%, abdominal discomfort in 8.6-13.3%, abdominal pain in 2.3-7.8%, nausea in 10.6-17.8%, dyspepsia in 8.4-8.9%, flatulence in 5.7-12.2%, vomiting in 2.9-4.4%, altered taste in 4.4%, and constipation in 3.3% of patients.
Adverse GI effects reported in <2% of patients receiving saquinavir hard gelatin or liquid-filled capsules alone or in conjunction with other antiretroviral agents include anorexia, abdominal distention, buccal mucosa ulceration, oral canker sores, cheilitis, dry mouth, dysphagia, abdominal colic, esophageal ulceration, esophagitis, eructation, bloodstained or discolored feces, frequent bowel movements, fecal incontinence, gastralgia, gastritis, GI reflux, GI ulcer, GI inflammation, intestinal obstruction, gingivitis, glossitis, hemorrhoids, infectious diarrhea, melena, painful defecation, parotid disorder, pruritus ani, /SRP: heartburn/, stomach upset, pelvic pain, rectal hemorrhage, salivary gland disorder, stomatitis, unpleasant taste, toothache, and tooth disorder.
Headache has occurred in 58.9% of adults with HIV infection receiving saquinavir liquid-filled capsules in conjunction with other antiretroviral agents. Depression has been reported in 2.7%, insomnia in 5.6%, and anxiety or libido disorder in 2.2% of patients receiving saquinavir liquid-filled capsules in conjunction with other antiretroviral therapy.
Adverse nervous system effects that have been reported in less than 2% of patients receiving saquinavir hard gelatin or liquid-filled capsules alone or in conjunction with other antiretroviral agents include ataxia, cerebral hemorrhage, confusion, seizures, dizziness, dysarthria, dysesthesia, facial numbness, facial pain, numbness of the extremities, hyperesthesia, hyperreflexia, hyporeflexia, light-headed feeling, myelopolyradiculoneuritis, paresthesia, peripheral neuropathy, prickly sensation, paresis, poliomyelitis, progressive multifocal leukoencephalopathy, spasms, tremor, and unconsciousness. Adverse psychologic effects reported in less than 2% of patients receiving the drug include agitation, amnesia, anxiety, behavior disturbances, excessive dreaming, euphoria, hallucination, irritability, lethargy, overdose effect, psychic disorder, psychosis, reduced intellectual ability, somnolence, and speech disorder. Serious adverse nervous system effects that have been reported rarely in clinical studies in patients receiving saquinavir alone or in conjunction with other antiretroviral agents which were considered to be at least possibly related to the study drugs include attempted suicide, episodes involving confusion, ataxia and weakness, and headache.
For more Drug Warnings (Complete) data for SAQUINAVIR (23 total), please visit the HSDB record page.

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Pharmacodynamics
Saquinavir exerts its antiviral activity by inhibiting an enzyme critical for the HIV-1 viral lifecycle. Like other protease inhibitors, saquinavir has a propensity for participating in drug interactions - use caution when administering saquinavir to patients maintained on other pharmaceutical agents as pharmacodynamic and pharmacokinetic interactions are common. Saquinavir is known to increase the QTc-interval in otherwise healthy individuals, and should therefore be used with caution in patients maintained on other QTc-prolonging medications or for whom prolongation of the QTc-interval may be of particular consequence (e.g. patients with pre-existing heart disease). Careful and regular monitoring of patient bloodwork is recommended, as saquinavir has been associated with the development of metabolic complications (e.g. diabetes mellitus, hyperlipidemia) and worsening of pre-existing liver disease.

C38H50N6O5

670.85

670.384

127779-20-8

Saquinavir mesylate;149845-06-7;Saquinavir-d9;1356355-11-7

441243

White to off-white solid powder

1.3±0.1 g/cm3

1015ºC at 760 mmHg

91.5ºC

567.7ºC

0mmHg at 25°C

1.646

6.4

5

7

13

49

1140

6

CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@H]([C@H](CC3=CC=CC=C3)NC(=O)[C@H](CC(=O)N)NC(=O)C4=NC5=CC=CC=C5C=C4)O

QWAXKHKRTORLEM-UGJKXSETSA-N

InChI=1S/C38H50N6O5/c1-38(2,3)43-37(49)32-20-26-14-7-8-15-27(26)22-44(32)23-33(45)30(19-24-11-5-4-6-12-24)41-36(48)31(21-34(39)46)42-35(47)29-18-17-25-13-9-10-16-28(25)40-29/h4-6,9-13,16-18,26-27,30-33,45H,7-8,14-15,19-23H2,1-3H3,(H2,39,46)(H,41,48)(H,42,47)(H,43,49)/t26-,27+,30-,31-,32-,33+/m0/s1

(2S)-N-[(2S,3R)-4-[(3S,4aS,8aS)-3-(tert-butylcarbamoyl)-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-3-hydroxy-1-phenylbutan-2-yl]-2-(quinoline-2-carbonylamino)butanediamide

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)

DMSO : ~100 mg/mL (~149.07 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (3.73 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.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (3.73 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.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (3.73 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.

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