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| Targets |
HIV; metabolite of Ritonavir
Ritonavir metabolite targets the HIV-1 protease enzyme, similar to the parent compound ritonavir. It binds to the active site of HIV-1 protease, preventing the processing of viral polyproteins into mature, infectious viral particles. It also interacts with cytochrome P450 3A4 (CYP3A4). |
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| ln Vitro |
The structural elucidation of metabolites of ritonavir and indinavir, HIV-protease inhibitor drugs, by liquid chromatography-electrospray ionization mass spectrometry is described. Ritonavir and indinavir were biotransformed separately by incubation with transplant quality human liver microsomes. The incubation mixture was then analyzed by HPLC coupled to ion trap (ITMS) and triple quadrupole mass analyzers. The metabolites retained most of the structural features of the parent molecules. Baseline chromatographic resolution of isobaric species by gradient elution HPLC permitted rapid structural identification of these metabolites. Both drugs were biotransformed primarily by oxidative and hydrolytic pathways to numerous metabolites that retained many of the features of the parent molecules. Triple quadrupole and ion trap mass spectrometry were applied jointly to thoroughly detect and thoroughly characterize these metabolites. Furthermore, retention-time and data-dependent scanning assured acquisition of detailed MS-MS spectra for rapid detection of metabolic pathways of ritonavir and indinavir. Comparison of the ITMS and triple quadrupole data showed qualitative and quantitative differences in the mass spectral patterns, suggesting that these instruments should be used in parallel to ensure comprehensive metabolite detection and characterization by LC-MS[1].
In vitro, ritonavir metabolite shows distinct biological activities compared to the parent drug, particularly in cancer models. It displays a unique CYP3A4 binding mode characterized by a 180° rotation in the active site and weaker enzyme inhibition. It is used to study the interaction between protease inhibitors and the protease enzyme. |
| ln Vivo |
In vivo, ritonavir metabolite is formed through extensive hepatic metabolism of ritonavir, primarily by CYP3A4. It circulates in the bloodstream and is excreted. Its in vivo activity is related to its parent compound's pharmacology. It has been identified as one of 26 ritonavir metabolites in mice.
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| Enzyme Assay |
The HIV-1 protease inhibition assay is performed using recombinant HIV-1 protease. The enzyme is incubated with a fluorogenic substrate and various concentrations of the ritonavir metabolite. The cleavage of the substrate is monitored by fluorescence. IC50 values are calculated from the inhibition curves.
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| Cell Assay |
Cells expressing HIV-1 proteins or infected with HIV-1 are cultured. The metabolite is added to the culture medium. Viral polyprotein processing is analyzed by Western blot using specific antibodies. The production of mature viral particles is assessed by p24 ELISA.
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| Animal Protocol |
Animal studies involve administering ritonavir to rodents or other species and analyzing plasma and tissue samples for the presence of the metabolite using LC-MS/MS. The metabolic profile is characterized to understand the biotransformation pathways of ritonavir.
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| ADME/Pharmacokinetics |
Ritonavir metabolite (MW 579.80) is a small molecule. It is formed in the liver via CYP3A4 metabolism. It has a boiling point of 822.4°C. Detailed pharmacokinetic properties of the metabolite itself are not separately characterized; it is studied as part of ritonavir's metabolic profile.
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| Toxicity/Toxicokinetics |
Comprehensive toxicology data for the ritonavir metabolite are not separately documented. It is considered a metabolite of an approved drug (ritonavir) and is generally regarded as safe at concentrations found in vivo during ritonavir therapy. It is not used as a therapeutic agent itself.
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| References |
[1]. Structural elucidation of metabolites of ritonavir and indinavir by liquid chromatography-mass spectrometry. J Chromatogr A . 2002 Oct 18;974(1-2):91-101.
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| Additional Infomation |
Ritonavir metabolite is primarily used as a reference standard in pharmaceutical research for analytical method development and metabolic studies. It is not an approved drug and is not in clinical trials. It serves as a valuable tool for studying the metabolism of ritonavir and the design of more effective protease inhibitors.
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| Molecular Formula |
C32H45N5O3S
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|---|---|
| Molecular Weight |
579.796406507492
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| Exact Mass |
579.324
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| CAS # |
176655-55-3
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| Related CAS # |
Ritonavir;155213-67-5
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| PubChem CID |
11467322
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| Appearance |
White to off-white solid powder
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| Boiling Point |
822.431ºC at 760 mmHg
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| Flash Point |
451.19ºC
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| Vapour Pressure |
0mmHg at 25°C
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| Index of Refraction |
1.587
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| LogP |
6.226
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
14
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| Heavy Atom Count |
41
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| Complexity |
787
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| Defined Atom Stereocenter Count |
4
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| SMILES |
CC(C)C1=NC(=CS1)CN(C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC2=CC=CC=C2)C[C@@H]([C@H](CC3=CC=CC=C3)N)O
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| InChi Key |
IQKWCORIMSRQGZ-AMEOFWRWSA-N
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| InChi Code |
InChI=1S/C32H45N5O3S/c1-21(2)29(36-32(40)37(5)19-26-20-41-31(35-26)22(3)4)30(39)34-25(16-23-12-8-6-9-13-23)18-28(38)27(33)17-24-14-10-7-11-15-24/h6-15,20-22,25,27-29,38H,16-19,33H2,1-5H3,(H,34,39)(H,36,40)/t25-,27-,28-,29-/m0/s1
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| Chemical Name |
(2S)-N-[(2S,4S,5S)-5-amino-4-hydroxy-1,6-diphenylhexan-2-yl]-3-methyl-2-[[methyl-[(2-propan-2-yl-1,3-thiazol-4-yl)methyl]carbamoyl]amino]butanamide
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| Synonyms |
176655-55-3; Ritonavir Metabolite; Desthiazolylmethyloxycarbonyl Ritonavir; Ritonavir metabolite M1; UNII-34F916N28Z; Ritonavir metabolite Desthiazolylmethyloxycarbonyl Ritonavir; A-98498; (2S)-N-[(2S,4S,5S)-5-amino-4-hydroxy-1,6-diphenylhexan-2-yl]-3-methyl-2-[[methyl-[(2-propan-2-yl-1,3-thiazol-4-yl)methyl]carbamoyl]amino]butanamide;
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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|---|---|
| Solubility (In Vivo) |
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.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *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). View More
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)] Oral Formulations
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). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7247 mL | 8.6237 mL | 17.2473 mL | |
| 5 mM | 0.3449 mL | 1.7247 mL | 3.4495 mL | |
| 10 mM | 0.1725 mL | 0.8624 mL | 1.7247 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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