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Ritonavir, better known as Norvir, (1hxw)

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Better Known as: Norvir (Kaletra when used in combination with Lopinavir)

  • Marketed By: Abbott Laboratories
  • Major Indication: Human Immunodeficiency Virus Infection
  • Drug Class: HIV Protease Inhibitor
  • Date of FDA Approval (Patent Expiration): 1996 (2013)
  • U.S. 2009 Sales: $310 Million
  • Importance: It is a powerful HIV Protease inhibitor. It is a major component of most HIV combination therapies because of its potent inhibition capacity of CYP3A4, increasing the bioavailability of other viral inhibitors.
  • See Pharmaceutical Drugs for more information about other drugs and disorders.

Mechanism of Action

When HIV infects a host, it directs the synthesis of several polyproteins. The maturation of the virus to its infectious form requires that these polyproteins be cleaved to their component proteins by HIV Protease. The subunits of come together to form a catalytic tunnel capable of binding the nascent peptides and cleaving them into their mature form. Buried within this tunnel lies , which contain the . These catalytic Asp residues carry out the hydrolytic cleavage of the viral polyproteins. Ritonavir to these conserved sequences within the HIV Protease tunnel, preventing the nascent polyproteins from entering. Unable to actively cleave the nascent proteins into their functional form, HIV is unable to mature and proliferate, allowing the patients immune system to fight off the infection more easily.[1][2]

Despite its ability to inhibit HIV Protease, Ritonavir is primarily used in combination therapies to inhibit the metabolizing enzyme, (CYP3A4). Ritonair binds with , inhibiting it. Since it is this enzyme which is responsible for metabolizing the other HIV Protease inhibitors, Ritonavir's inhibition of CYP3A4 increases the bioavilaibility of other antiviral medications.[3]

Drug Resistance

The biggest difficulty with treating HIV is the rapidity at which it mutates and becomes resistant to treatments. To view a comprehensive and interactive analysis of the mutations which confer drug resistance to HIV Protease, See: HIV Protease Inhibitor Resistance Profile


HIV Protease Inhibitor Pharmacokinetics
Parameter Ritonavir Tipranavir Indinavir Saquinavir Amprenavir Fosamprenavir Lopinavir Darunavir Atazanavir Nelfinavir
Tmax (hr) 4.4 ~3 1.5 3.7 .98 1.5-4 2 .5 2-4 3.1
Cmax (ng/ml) 13120 14600 8100 2297 4901 4820 11.9 2730 ~4393 4701
Bioavailability (%) -- -- 65 4 -- -- -- -- 68 20-80
Protein Binding (%) 99 >99 61 98 90 90 99 95 86 98
T1/2 (hr) 4.8 4.2 1.2 4.5 5.5 7.7 6.1 29.4 5.3 3.3
AUC (ng/ml/hr) 128100 46500 20900 13467 11999 35000 117600 4746 ~26045 31906
Clearance (L/h) ~8.4 32.4 49.5 36.7 56.8 84.4 1.7 32.8 13.6 37.3
Dosage (mg) 600 600 800 1000 600 1400 280 400 400 1250
Metabolism Hepatic (CYP3A4 & CYP2C19) Hepatic (CYP3A4) Hepatic (CYP3A4) Hepatic (CYP3A4 & CYP3A5) Hepatic (CYP3A4) Hepatic (CYP3A4) Hepatic (CYP3A4) Hepatic (CYP3A4) Hepatic (CYP3A4) Hepatic (CYP3A4)

For Pharmacokinetic Data References, See: References


  1. Spinelli S, Liu QZ, Alzari PM, Hirel PH, Poljak RJ. The three-dimensional structure of the aspartyl protease from the HIV-1 isolate BRU. Biochimie. 1991 Nov;73(11):1391-6. PMID:1799632
  2. Tie Y, Kovalevsky AY, Boross P, Wang YF, Ghosh AK, Tozser J, Harrison RW, Weber IT. Atomic resolution crystal structures of HIV-1 protease and mutants V82A and I84V with saquinavir. Proteins. 2007 Apr 1;67(1):232-42. PMID:17243183 doi:10.1002/prot.21304
  3. Sevrioukova IF, Poulos TL. Structure and mechanism of the complex between cytochrome P4503A4 and ritonavir. Proc Natl Acad Sci U S A. 2010 Oct 11. PMID:20937904 doi:10.1073/pnas.1010693107

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