| Identification | More | [Name]
Ritonavir | [CAS]
155213-67-5 | [Synonyms]
1,3-THIAZOL-5-YLMETHANOL
1,3-thiazol-5-ylmethyl n-[(2s,3s,5r)-3-hydroxy-5-[[(2s)-3-methyl-2-[[methyl-[(2-propan-2-yl-1,3-thiazol-4-yl)methyl]carbamoyl]amino]butanoyl]amino]-1,6-diphenyl-hexan-2-yl]carbamate
5-HYDROXYMETHYLTHIAZOLE
CHEMBRDG-BB 4050354
RARECHEM AL BD 1261
RITONAVIR
THIAZOL-5-YL-METHANOL
THIAZOLE-5-METHANOL
ABT-538
Liponavir Core
(3S,4S,6S,9S)-4-Hydroxy-12-methyl-9-(1-methylethyl)-13-[2-(1-methylethyl)-4-thiazolyl]-8,11-dioxo-3,6-bis(phenylmethyl)-2,7,10,12-tetraazatridecanoic acid, 5-thiazolylmethyl Ester
A 84538
Norvi
2,4,7,12-Tetraazatridecan-13-oic acid, 10-hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-, 5-thiazolylmethyl ester, (5S,8S,10S,11S)-(9CI)
2,4,7,12-Tetraazatridecan-13-oic acid, 10-hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-, 5-thiazolylmethyl ester, [5S-(5R*,8R*,10R*,11R*)]-
Abbott 84538
Norvir
NSC 693184
1,3-Thiazol-5-ylmethyl N-[(2S,3S,5R)-3-hydroxy-5-[[(2S)-3-methyl-2-[[methyl-[(2-propan-2-yl-1,3-thiazol-4-yl)methyl]carbamoyl]amino]butanoyl]amino]-1,6-diphenyl-hexan-2-yl]carbamate
Ethinyl Estradiol, Powder | [EINECS(EC#)]
605-001-5 | [Molecular Formula]
C4H5NOS | [MDL Number]
MFCD04115732 | [Molecular Weight]
115.15 | [MOL File]
155213-67-5.mol |
| Chemical Properties | Back Directory | [Appearance]
White Powder | [Melting point ]
120-122°C | [Boiling point ]
947.0±65.0 °C(Predicted) | [density ]
1.239±0.06 g/cm3(Predicted) | [Fp ]
2℃ | [storage temp. ]
room temp | [solubility ]
DMSO: soluble10mg/mL (clear solution, warmed) | [form ]
powder | [pka]
11.47±0.46(Predicted) | [color ]
white to beige | [Water Solubility ]
5mg/L(ms) | [Usage]
A selective HIV protease inhibitor | [Merck ]
14,8238 | [BCS Class]
2,4 | [Stability:]
Stable for 1 year from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20° for up to 2 months. | [InChIKey]
NCDNCNXCDXHOMX-XGKFQTDJSA-N | [CAS DataBase Reference]
155213-67-5(CAS DataBase Reference) |
| Safety Data | Back Directory | [Hazard Codes ]
Xi | [Risk Statements ]
R36/38:Irritating to eyes and skin . | [Safety Statements ]
S26:In case of contact with eyes, rinse immediately with plenty of water and seek medical advice .
S37/39:Wear suitable gloves and eye/face protection . | [RIDADR ]
UN 1648 3 / PGII | [WGK Germany ]
3 | [RTECS ]
XA5310000 | [HS Code ]
29341000 | [Hazardous Substances Data]
155213-67-5(Hazardous Substances Data) |
| Hazard Information | Back Directory | [Description]
Norvir was launched in Germany, the UK and US for treatment of advanced
HIV in combination with antiretroviral nucleoside analogs in a record 72 days by the
FDA. It is an inhibitor of HIV aspartic protease which is critical in the processing of a
propeptide into the gag, gag-pol gene products and the protease itself. This inhibition
results in the release of non-infectous immature virus particles. It is greater than
500-fold more selective for viral aspartic protease than the human version, has good
oral bioavailability and may increase the bioavailability of other protease inhibitors.
Ritonavir was able to increase the CD4 and CD8 lymphocyte count as well as reduce
viral RNA. It is more potent than saqunavir and comparible in potency to zidovudine
and lamivudine. | [Chemical Properties]
White or almost white powder. | [Originator]
Abbott (USA) | [Uses]
A selective HIV protease inhibitor | [Uses]
Protease inhibitor; antiviral (HIV). | [Uses]
Ritonivir is an HIV protease inhibitor (EC50 = 25 nM) that also inhibits CYP3A4, the primary cytochrome P450 isoform that metabolizes protease inhibitors. Through CYP3A4 inhibition, low doses of ritonivir can reduce the metabolism of concomitantly administered protease inhibitiors, enhancing their bioavailability and efficacy.[Cayman Chemical] | [Definition]
ChEBI: An L-valine derivative that is an antiretroviral drug from the protease inhibitor class used to treat HIV infection and AIDS, it is often used as a fixed-dose combination with another protease inhibitor, lopinavir. Also used in combination
with dasabuvir sodium hydrate, ombitasvir and paritaprevir (under the trade name Viekira Pak) for treatment of chronic hepatitis C virus genotype 1 infection as well as cirrhosis of the liver. | [Indications]
Although ritonavir (Norvir) 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. | [Brand name]
Norvir (Abbott). | [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. | [General Description]
Ritonavir belongs to the group of protease inhibitors, which block the part of HIV called protease. Its mode of action involves binding to the protease active site and inhibiting the activity of the enzyme. | [Pharmaceutical Applications]
A synthetic chemical available for oral use as soft capsules
and a liquid formulation. It is now almost exclusively used as
a pharmacokinetic enhancer to ‘boost’ the pharmacokinetic
properties of HIV protease inhibitors in the treatment of
HIV-1 infection in patients over 1 month in age. | [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. | [Clinical Use]
Treatment of HIV infection in adults and children >1 month old (in
combination with other antiretroviral agents) | [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]
Potentially hazardous interactions with other drugs
Alpha-blockers: concentration of alfuzosin increased
- avoid.
Aminophylline: concentration of aminophylline
reduced.
Analgesics: buprenorphine and NSAID levels
may be increased (risk of toxicity) - avoid
dextropropoxyphene and piroxicam; methadone,
pethidine and possibly morphine concentration
reduced; increased alfentanil, fentanyl and toxic
pethidine metabolite concentration - avoid with
pethidine.
Anthelmintics: possibly reduces active metabolite of
albendazole, consider increasing albendazole dose.
Anti-arrhythmics: increased concentration of
amiodarone, flecainide and propafenone (increased
risk of ventricular arrhythmias) - avoid; possible
increased risk of arrhythmias with disopyramide;
avoid with dronedarone.
Antibacterials: rifabutin concentration increased
(risk of uveitis) - reduce rifabutin dose;
concentration of clarithromycin and other macrolides
increased - reduce dose of clarithromycin in renal
impairment; concentration reduced by rifampicin;
concentration of both drugs may be increased in
combination with fusidic acid - avoid; AUC of
bedaquiline increased by 22%, avoid if ritonavir given
for >14 days; concentration of delamanid increased.
Anticoagulants: anticoagulant effect of coumarins
and phenindione possibly increased; effect of
warfarin may be enhanced or reduced; avoid with
apixaban; concentration of rivaroxaban increased -
avoid.
Antidepressants: SSRIs and tricyclic concentrations
possibly increased; concentration reduced by St
John’s wort - avoid; possibly reduced paroxetine
concentration; increased side effects with trazodone.
Antiepileptics: carbamazepine fosphenytoin
and phenytoin concentration may be increased;
concentration reduced by fosphenytoin, phenytoin;
concentration of lamotrigine and valproate reduced.
Antifungals: in combination with itraconazole or
ketoconazole concentration of both drugs may be
increased; concentration increased by fluconazole;
voriconazole concentration reduced - avoid.
Antimalarials: use artemether/lumefantrine
with caution; concentration possibly reduced by
mefloquine; concentration of quinine increased.
Antimuscarinics: avoid with darifenacin and
tolterodine; reduce dose of fesoterodine;
concentration of solifenacin possibly increased.
Antipsychotics: concentration of lurasidone,
pimozide, quetiapine, clozapine and possibly other
antipsychotics may be increased (risk of toxicity) -
avoid; possibly inhibits metabolism of aripiprazole
- reduce aripiprazole dose; olanzapine concentration
reduced.
Antivirals: concentration of both drugs reduced with
boceprevir; didanosine and ritonavir should be taken
2.5 hours apart; indinavir, maraviroc and saquinavir
levels increased; increased risk of toxicity with
efavirenz - monitor LFTs, avoid high dose ritonavir
with atripla; concentration of simeprevir increased -
avoid; possibly reduces telaprevir concentration.
Anxiolytics and hypnotics: levels of many of them
increased (risk of extreme sedation and respiratory
depression) - avoid alprazolam, diazepam,
flurazepam, midazolam, zolpidem; concentration of
buspirone increased.
Avanafil: concentration of avanafil significantly
increased - avoid.
Bosentan: increases bosentan concentration.
Calcium-channel blockers: levels of calciumchannel blockers possibly increased - avoid with
lercanidipine.
Ciclosporin: levels possibly increased by ritonavir.
Cilostazol: possibly increases cilostazol
concentration.
Colchicine: possibly increases risk of colchicine
toxicity, avoid in hepatic or renal impairment.
Corticosteroids: possibly increased corticosteroid
concentration; increased concentration of inhaled/
intranasal budesonide and fluticasone.
Cytotoxics: increases concentration of afatinib
(separate ritonavir by 6-12 hours); possibly
increases concentration of axitinib, panobinostat
and pazopanib, reduce dose of axitinib, panobinostat
and pazopanib; possibly increases concentration of
bosutinib, cabazitaxel, ceritinib and olaparib - avoid
or reduce dose of bosutinib, cabazitaxel, ceritinib
and olaparib; possibly increases concentration of
cabozantinib and vinblastine; possibly increases
concentration of crizotinib, everolimus, nilotinib,
simeprevir and vinflunine - avoid; avoid with
dasatinib and lapatinib; concentration of ibrutinib
possibly increased - reduce dose of ibrutinib;
concentration of docetaxel possibly increased - avoid
or reduce docetaxel dose; reduce dose of ruxolitinib;
possibly increases concentration of ponatinib
- consider reducing initial dose of ponatinib;
concentration of paclitaxel increased.
Dapoxetine: avoid concomitant use.
Diuretics: eplerenone concentration increased -
avoid.
Domperidone: possible increased risk of ventricular
arrhythmias - avoid.
Ergot alkaloids: risk of ergotism - avoid.
Guanfacine: possibly increases guanfacine dose -
halve guanfacine dose.
5HT1
agonists: concentration of eletriptan increased
- avoid.
Ivabradine: ivabradine concentration possibly
increased - avoid.
Lipid-lowering drugs: increased risk of myopathy
with rosuvastatin and simvastatin - avoid; possibly
increased risk of myopathy with atorvastatin; avoid
with lomitapide.
Naloxegol: possibly increases naloxegol concentration
- avoid.
Oestrogens and progestogens: metabolism
accelerated (contraceptive effect reduced).
Orlistat: absorption of ritonavir possibly reduced.
Ranolazine: possibly increases ranolazine
concentration - avoid.
Sildenafil: concentrations of sildenafil significantly
increased - avoid.
Tacrolimus: levels possibly increased by ritonavir.
Tadalafil: concentrations of tadalafil increased -
avoid.
Theophylline: metabolism accelerated, theophylline
levels reduced.
Ticagrelor: possibly increases concentration of
ticagrelor - avoid.
Ulipristal: contraceptive effect reduced - avoid.
Vardenafil: possibly increased vardenafil
concentration - avoid. | [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. | [storage]
Store at -20°C | [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 |
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