155213-67-5 Usage
Description
Ritonavir, also known as Norvir, is a potent HIV protease inhibitor that belongs to the group of protease inhibitors. It is an L-valine derivative with a unique chemical structure that allows it to inhibit the activity of HIV aspartic protease, a critical enzyme in the processing of viral proteins. Ritonavir's mode of action involves binding to the protease active site, thereby blocking the formation of mature, infectious virus particles. It is highly selective for viral protease over the human version and has good oral bioavailability. Additionally, Ritonavir is a CYP3A inhibitor, which allows it to reduce the metabolism of concomitantly administered protease inhibitors, enhancing their bioavailability and efficacy.
Uses
Used in HIV Treatment:
Ritonavir is used as an antiretroviral agent for the treatment of HIV-1-infected patients. It is often administered in combination with other antiretroviral agents to enhance the overall therapeutic effect. Ritonavir's ability to inhibit HIV protease results in the release of non-infectious immature virus particles, thereby reducing the viral load and increasing the CD4 and CD8 lymphocyte count.
Used in Hepatitis C Treatment:
Ritonavir is also used in combination with dasabuvir sodium hydrate, ombitasvir, and paritaprevir (under the trade name Viekira Pak) for the treatment of chronic hepatitis C virus genotype 1 infection, as well as cirrhosis of the liver. Its role as a CYP3A inhibitor helps to improve the bioavailability of these drugs, leading to better treatment outcomes.
Used in Drug Delivery Systems:
Ritonavir's role as a CYP3A inhibitor allows it to be used in drug delivery systems to enhance the bioavailability of other protease inhibitors. By reducing the metabolism of these drugs, low doses of ritonavir can improve the overall efficacy of combination antiretroviral therapy.
Used in Fixed-Dose Combinations:
Ritonavir is often used as a fixed-dose combination with another protease inhibitor, lopinavir, to treat HIV infection and AIDS. This combination therapy helps to improve the patient's adherence to the treatment regimen and provides a more potent and effective treatment option.
Originator
Abbott (USA)
Indications
Ritonavir is a prescription medicine approved by the U.S. Food and Drug Administration (FDA) for the treatment of HIV infection in adults and children older than 1 month. Although Ritonavir is a potent inhibitor of HIV-1 and HIV-2 protease, it is not well tolerated in higher doses. It is mainly used in low doses to increase blood levels of other protease inhibitors and to extend their dosing interval. Ritonavir is more commonly associated with gastrointestinal side effects, altered taste sensation, paresthesias, and hypertriglyceridemia than are other protease inhibitors. Pancreatitis may occur in the presence or absence of hypertriglyceridemia.
Antimicrobial activity
Ritonavir is active against HIV-1 and, to a lesser extent, HIV-2.
Acquired resistance
At antiretroviral doses resistance is associated with the presence
of specific amino acid substitutions in the HIV protease
at positions 82 and 84. Concern about the risk for
selection of ritonavir resistance when used at a subtherapeutic
‘booster’ dose has so far not been borne out by clinical
experience.
Biological Activity
Ritonavir is an HIV protease inhibitor. It inhibits recombinant HIV-1 protease by 79% when used at a concentration of 0.5 nM. It inhibits HIV-13B-induced cell death in MT-4 human T cell leukemia cells (EC50 = 25 nM) as well as cell death induced by HIV-1LAI, HIV-2ROD, and HIV-2EHO in human MT-2 cells (IC50s = 0.045, 0.13, and 0.24 μM, respectively). Ritonavir also inhibits the cytochrome P450 (CYP) isoform CYP3A (IC50 = 0.14 μM). It inhibits CYP-mediated oxidative metabolism of the HIV protease inhibitors saquinavir , indinavir , nelfinavir , and amprenavir in rat and human liver microsomes in a concentration-dependent manner. Ritonavir (10 mg/kg) also prevents decreases in plasma levels of these four compounds in rats. Formulations containing ritonavir have been used in the treatment of HIV-1 infection.
Biochem/physiol Actions
Ritonavir is an HIV protease inhibitor now used frequently as a booster of other protease inhbitors. Ritonavir inhibits cytochrome P450-3A4 (CYP3A4), a liver enzyme that normally metabolizes protease inhibitors. It has also been investigated as a possible anti-cancer agent.
Mechanism of action
Because of the strong CYP450-inhibiting effects of ritonavir, the drug has found value when used in
fixed-dosage combinations with other PIs to block their metabolism and act as a booster for these drugs
(lopinavir/ritonavir and tipranavir/ritonavir). In these cases, ritonavir is used in a subtherapeutic dose but
boosts the effectiveness of the coadministered drug. The utilization of ritonavir in a therapeutic dose for
treating HIV infections appears to be decreasing, but its utilization as a booster drug is finding favor.
Pharmacokinetics
Oral absorption: Not known/available
Cmax 600 mg twice daily: c. 11.2 mg/L
Cmin 600 mg twice daily: c. 3.7 mg/L
Plasma half-life: c. 3–5 h
Volume of distribution: c. 0.3–0.6 L/kg
Plasma protein binding: c. 97%
Absorption and distribution
Fasting and high-fat meals had no appreciable effect on oral absorption. It penetrates poorly into the CNS. The semen:plasma ratio is <0.04. It is distributed into breast milk.
Metabolism and excretion
Four oxidized metabolites have been identified, the major of which retains antiretroviral activity. Around 11% of the dose is excreted in urine, 4% as unchanged drug. The remainder is found in feces. Metabolites are eliminated primarily via the feces.
No dose adjustment is recommended in mild to moderate hepatic impairment. It should not be given to patients with severe hepatic impairment, nor should it be given as a pharmacokinetic enhancer to patients with decompensated liver disease.
Side effects
Full (antiretroviral) doses are associated with nausea, vomiting,
diarrhea and fatigue in >20% of subjects. The degree to which
ritonavir at low dose is associated with specific adverse events
is uncertain. In HIV-negative healthy volunteers given ‘booster’
doses of 100 mg every 12 h, the concentration of total cholesterol,
low-density cholesterol and triglycerides all increased, and
the concentration of high-density cholesterol concentration fell.
Drug interactions
Ritonavir-boosted nirmatrelvir has significant drug-drug interactions, primarily due to the ritonavir component of the combination. Boosting with ritonavir, which is a strong CYP3A inhibitor and a P-glycoprotein inhibitor, is required to increase the exposure of nirmatrelvir to a concentration that is effective against SARS-CoV-2. However, it may also increase concentrations of certain concomitant medications, thereby increasing the potential for serious and sometimes life-threatening drug toxicities. Additionally, ritonavir is an inhibitor, inducer, and substrate of various other drug-metabolizing enzymes and/or drug transporters.
Metabolism
Ritonavir is extensively metabolised in the liver mainly by
cytochrome P450 isoenzymes CYP3A4 and to a lesser
extent by CYP2D6. Five metabolites have been identified
and the major metabolite has antiviral activity, but
concentrations in plasma are low.
About 86% of a dose is eliminated through the faeces
(both as unchanged drug and as metabolites) and about
11% is excreted in the urine.
References
1) Lea and Faulds (2018)?Ritonavir;?Drugs?52?541
2) Koudriakova?et al.?(1998)?Metabolism of the Human Immunodeficiency Virus Protease Inhibitors Indinavir and Ritonavir by Human Intestinal Microsomes and Expressed Cytochrome P4503A4/3A5: Mechanism-Based Inactivation of Cytochrome P3503A by Ritonavir;?Drug Metab. Dispos.?26?552
3) Rock?et al.?(2014)?Characterization of Ritonavir-Mediated Inactivation of Cytochrome P450 3A4;?Mol. Pharmacol.?86?665
Check Digit Verification of cas no
The CAS Registry Mumber 155213-67-5 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,5,5,2,1 and 3 respectively; the second part has 2 digits, 6 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 155213-67:
(8*1)+(7*5)+(6*5)+(5*2)+(4*1)+(3*3)+(2*6)+(1*7)=115
115 % 10 = 5
So 155213-67-5 is a valid CAS Registry Number.
InChI:InChI=1/C37H48N6O5S2/c1-24(2)33(42-36(46)43(5)20-29-22-49-35(40-29)25(3)4)34(45)39-28(16-26-12-8-6-9-13-26)18-32(44)31(17-27-14-10-7-11-15-27)41-37(47)48-21-30-19-38-23-50-30/h6-15,19,22-25,28,31-33,44H,16-18,20-21H2,1-5H3,(H,39,45)(H,41,47)(H,42,46)/t28-,31-,32-,33-/m0/s1
155213-67-5Relevant articles and documents
Preparation method of ritonavir
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Paragraph 0004; 0005; 0007; 0008; 0010, (2021/10/13)
The invention provides a preparation method shown I, N - [(2S, 3S, 5R) -3 - hydroxyl -5 - [(2S) -3 - methyl -2 - [[methyl - [(2 - isopropyl -1, 3 - thiazole -4 - yl) methyl] carbamoyl] amino] -1, 6 - diphenyl - hexyl -2 -] carbamic acid 5 - thiazolyl methyl ester. The invention provides a new method for preparing ritonavir.
Preparation method of ritonavir
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, (2019/03/08)
The invention relates to the technical field of medicine, in particular to a preparation method of ritonavir. According to the preparation method of the ritonavir, (2-isopropyl thiazole-4-yl)-nitrogen-methyl methylamine is taken as a raw material, and the ritonavir is synthesized through a three-step reaction; a urea bond is built by trichloroethanol chloroformate, paratoluensulfonyl chloride which is cheap and easy to obtain is adopted as a condensing agent for amide, the ritonavir is synthesized with the high yield, and the yield of the ritonavir is 79%; and compared with an existing preparation method, the preparation method has the advantages of low cost, environment friendliness, easy scale production and the like, and has good application prospects.
A method of preparing anti HIV drug ritonavir
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, (2017/08/25)
The invention discloses a method for preparing anti-HIV medicine ritonavir and belongs to the technical field of medicines. In conditions of proper temperature, taking weak base as acid-binding agent and certain organic solvent, N-[N(-methyl-N-[(2-isopropyl-4-thiazolyl) methyl] amino-carbonyl]-L-valine and thionyl chloride are reacted to produice N(-[N-methyl-N-[(2-isopropyl-4-thiazolyl) methyl] amino-carbonyl]-L-valine acyl chloride, which is not required to be purified and can be directly subjected to amide reaction with (2s, 3s, 5s)-5-amino-2-((i)N(/i)-((5-thiazolyl)-methoxycarbonyl group) amino)-1, 6-diphenyl-3-hydroxy hexane at a room temperature, so as to obtain ritonavir; the mole ratio of the N-[N-methyl-N-[(2-isopropyl-4-thiazolyl) methyl] amino-carbonyl]-L-valine to thionyl chloride is 1:1 to 1:8; the mole ratio of the N-[N-methyl-N-[(2-isopropyl-4-thiazolyl) methyl] amino-carbonyl]-L-valine acyl chloride to weak base is 1:1 to 1:15. The method has the advantages that the price of thionyl chloride is low, the material cost is reduced, the production pollution is low, the pollution can be changed into soluble effluent brine, the method is simple to operate, the product yield is high, and the method is easy for separation and purification, and is applicable to industrial production.
