PXR; HIV protease (IC50 = 14.6 ng/mL)

Amprenavir has an enzyme inhibition constant (Ki = 0.6 nM) that is within the other protease inhibitors' Ki range. The in vitro 50% inhibitory concentration (IC50) of amprenavir against clinical HIV isolates of wild type is 14.6 +/- 12.5 ng/mL (mean +/- SD) [1]. By preventing MMP proteolytic activation, amprenavir directly inhibited the invasion of Huh-7 hepatocarcinoma cell lines [2].

Amprenavir was able to encourage the remission of hepatocarcinoma growth in vivo through anti-angiogenetic and general anti-tumor activities, through independent pathways related to PI3K/AKT, which is currently one of the more plausible theories to explain the anti-tumor effects of the various protease inhibitors[2]. PXR was effectively activated and PXR target gene expression was induced both in vitro and in vivo by amprenavir. In mice of the wild type, but not in mice lacking PXR, a brief exposure to amprenavir markedly raised the levels of atherogenic low-density lipoprotein cholesterol and plasma total cholesterol [3]. The recommended dosage of amprenavir for adults and children is 1200 mg twice daily for adults, 20 mg/kg twice daily for children under the age of 13, or 15 mg/kg three times daily for adolescents under the weight of 50 kg[1].

Amprenavir induced the expression of the PXR target gene in LS180 intestinal cells and HepaRG hepatoma cells.

Absorption, Distribution and Excretion
Rapidly absorbed after oral administration in HIV-1-infected patients with a time to peak concentration (Tmax) typically between 1 and 2 hours after a single oral dose. The absolute oral bioavailability of amprenavir in humans has not been established.
Amprenavir is absorbed rapidly after oral administration. Taking amprenavir with a standard meal reduces the plasma AUC by only about 13%, but high-fat meals may have greater effects and should be avoided.
Only minimal amounts of amprenavir are eliminated unchanged in urine or feces; less than 3% of a dose is eliminated unchanged in urine. Following a single oral dose of radiolabeled amprenavir, approximately 14% of the dose is eliminated in urine and 75% is eliminated in feces; 2 metabolites account for more than 90% of radioactivity in feces.
Distribution of amprenavir into body tissues and fluids has not been fully characterized. Studies in rats indicate that amprenavir is distributed to a variety of tissues following oral administration. The apparent volume of distribution of amprenavir in healthy adults is approximately 430 L.
It is not known whether amprenavir crosses the human placenta; however, the drug crosses the placenta in rats. Information from an ex vivo human placental model for transplacental passage indicates that amprenavir crosses the human placenta. Although it is not known whether amprenavir is distributed in human milk, the drug is distributed into milk in rats.
In patients with hepatic impairment, the peak plasma concentration and AUC of amprenavir may be increased. In adults with moderate cirrhosis who received a single 600-mg oral dose of amprenavir given as liquid-filled capsules, the AUC (0-4 hours) of the drug averaged 25.76 ug hour/mL compared with 12 ug hour/ml in healthy adults. In adults with severe cirrhosis who received the same dose, peak plasma concentrations averaged 9.43 ug/ml and the AUC (0-4 hours) averaged 38.66 ug hour/ml compared with 4.9 ug/ml or 12 ug hour/ml, respectively, in healthy adults.

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Metabolism / Metabolites
Hepatic. Amprenavir is metabolized in the liver by the cytochrome P450 3A4 (CYP3A4) enzyme system. The 2 major metabolites result from oxidation of the tetrahydrofuran and aniline moieties. Glucuronide conjugates of oxidized metabolites have been identified as minor metabolites in urine and feces.
The metabolic fate of amprenavir has not been fully determined, but the drug is metabolized in the liver. Amprenavir is metabolized principally by the cytochrome P450 (CYP) isoenzyme 3A4. The 2 major metabolites of the drug result from oxidation of the tetrahydrofuran and aniline moieties; glucuronide conjugates of oxidized metabolites have been identified as minor metabolites in urine and feces.
Hepatic. Amprenavir is metabolized in the liver by the cytochrome P450 3A4 (CYP3A4) enzyme system. The 2 major metabolites result from oxidation of the tetrahydrofuran and aniline moieties. Glucuronide conjugates of oxidized metabolites have been identified as minor metabolites in urine and feces.
Half Life: 7.1-10.6 hours

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Biological Half-Life
7.1-10.6 hours
The plasma elimination half-life of amprenavir in HIV-infected adults with normal renal and hepatic function ranges from 7.1-10.6 hours.

Protein Binding
Very high (90%). Amprenavir has the highest affinity for alpha(1)-acid glycoprotein.

[1]. Clinical pharmacology and pharmacokinetics of amprenavir. Ann Pharmacother. 2002 Jan;36(1):102-18.

[2]. Amprenavir inhibits the migration in human hepatocarcinoma cell and the growth of xenografts. J Cell Physiol. 2013 Mar;228(3):640-5.

[3]. Pregnane X Receptor Mediates Dyslipidemia Induced by the HIV Protease Inhibitor Amprenavir in Mice. Mol Pharmacol. 2013 Jun;83(6):1190-9.

[4]. 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.

Amprenavir is a tetrahydrofuryl ester, a sulfonamide and a carbamate ester. It has a role as a HIV protease inhibitor and an antiviral drug.
Amprenavir is a protease inhibitor used to treat HIV infection.
Amprenavir is a Protease Inhibitor. The mechanism of action of amprenavir is as a HIV Protease Inhibitor, and Cytochrome P450 3A4 Inhibitor, and Cytochrome P450 3A4 Inducer, and P-Glycoprotein Inducer.
Amprenavir is a synthetic derivative of hydroxyethylamine sulfonamide that selectively binds to and inhibits human immunodeficiency virus (HIV) protease.
Amprenavir is only found in individuals that have used or taken this drug. It is a protease inhibitor used to treat HIV infection.Amprenavir inhibits the HIV viral proteinase enzyme which prevents cleavage of the gag-pol polyprotein, resulting in noninfectious, immature viral particles.
See also: Fosamprenavir Calcium (active moiety of); Fosamprenavir Sodium (is active moiety of).

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Drug Indication
For the treatment of HIV-1 infection in combination with other antiretroviral agents.
FDA Label
Agenerase, in combination with other antiretroviral agents, is indicated for the treatment of protease inhibitor (PI) experienced HIV-1 infected adults and children above the age of 4 years. Agenerase capsules should normally be administered with low dose ritonavir as a pharmacokinetic enhancer of amprenavir (see sections 4. 2 and 4. 5). The choice of amprenavir should be based on individual viral resistance testing and treatment history of patients (see section 5. 1). The benefit of Agenerase boosted with ritonavir has not been demonstrated in PI nave patients (see section 5. 1)

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Mechanism of Action
Amprenavir inhibits the HIV viral proteinase enzyme which prevents cleavage of the gag-pol polyprotein, resulting in noninfectious, immature viral particles.
Amprenavir acts by reversibly binding to the active site of HIV protease. This prevents polypeptide processing and subsequent viral maturation.
Although the complete mechanism(s) of antiviral activity of amprenavir has not been fully elucidated, amprenavir apparently inhibits replication of human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) by interfering with HIV protease. The drug, therefore, exerts a virustatic effect against retroviruses by acting as an HIV protease inhibitor.
Amprenavir is a selective, competitive, reversible inhibitor of HIV protease. HIV protease, an aspartic endopeptidase that functions as a homodimer, plays an essential role in the HIV replication cycle and the formation of infectious virus. During HIV replication, HIV protease cleaves viral polypeptide products of the gag and gag-pol genes (i.e., p55 and p160) to form structural proteins of the virion core (i.e., p17, p24, p9, and p7) and essential viral enzymes (i.e., reverse transcriptase, integrase, protease). By interfering with the formation of these essential proteins and enzymes, amprenavir blocks maturation of the virus and causes the formation of nonfunctional, immature, noninfectious virions. Amprenavir is active in both acutely and chronically infected cells since it targets the HIV replication cycle after translation and before assembly. Thus, the drug is active in a subset of chronically infected cells (e.g., monocytes, macrophages) that generally are not affected by nucleoside reverse transcriptase inhibitors (e.g., abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine). Amprenavir does not affect early stages of the HIV replication cycle; however, the drug interferes with the production of infectious HIV and limits further infectious spread of the virus.
Unlike nucleoside reverse transcriptase inhibitors, the antiretroviral activity of amprenavir does not depend on intracellular conversion to an active metabolite. Amprenavir and other HIV protease inhibitors (e.g., indinavir, lopinavir, nelfinavir, ritonavir, saquinavir) act at a different stage of the HIV replication cycle than other currently available antiretroviral agents, including nucleoside reverse transcriptase inhibitors and nonnucleoside reverse transcriptase inhibitors.
Amprenavir is a highly specific inhibitor of HIV protease. Amprenavir has low affinity for human aspartic endopeptidases such as pepsin, renin, gastricin, cathepsin D, and cathepsin E. Results of in vitro studies using MT-4 cells indicate that amprenavir is not cytotoxic at concentrations up to 100 um.

C25H35N3O6S

505.63

505.224

C, 59.39; H, 6.98; N, 8.31; O, 18.99; S, 6.34

161814-49-9

Amprenavir-d4;1217661-20-5;Amprenavir-d4-1;2738376-78-6

65016

White to off-white solid powder

1.3±0.1 g/cm3

722.5±70.0 °C at 760 mmHg

72-74ºC

390.8±35.7 °C

0.0±2.5 mmHg at 25°C

1.602

4.68

3

8

12

35

745

3

S(C1C([H])=C([H])C(=C([H])C=1[H])N([H])[H])(N(C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H])C([H])([H])[C@]([H])([C@]([H])(C([H])([H])C1C([H])=C([H])C([H])=C([H])C=1[H])N([H])C(=O)O[C@]1([H])C([H])([H])OC([H])([H])C1([H])[H])O[H])(=O)=O

YMARZQAQMVYCKC-OEMFJLHTSA-N

InChI=1S/C25H35N3O6S/c1-18(2)15-28(35(31,32)22-10-8-20(26)9-11-22)16-24(29)23(14-19-6-4-3-5-7-19)27-25(30)34-21-12-13-33-17-21/h3-11,18,21,23-24,29H,12-17,26H2,1-2H3,(H,27,30)/t21-,23-,24+/m0/s1

[(3S)-oxolan-3-yl] N-[(2S,3R)-4-[(4-aminophenyl)sulfonyl-(2-methylpropyl)amino]-3-hydroxy-1-phenylbutan-2-yl]carbamate

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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.94 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 (4.94 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 (4.94 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.)