Ritonavir: Difference between revisions

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<applet  load="" size="480" color="" frame="true"  spin="on" Scene ="Ritonavir/Ritonavir/1" align="right" caption="Ritonavir, better known as Norvir, ([[1hxw]])"/>
<StructureSection load='' size='340' side='right' caption='Ritonavir, better known as Norvir, ([[1hxw]])' scene='Ritonavir/Ritonavir/1'>
===Better Known as: Norvir (Kaletra when used in combination with Lopinavir)===
===Better Known as: Norvir (Kaletra when used in combination with Lopinavir)===
* Marketed By: Abbott Laboratories<br />
* Marketed By: Abbott Laboratories<br />
Line 7: Line 7:
* U.S. 2009 Sales: $310 Million
* 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.  
* 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.  
* The following is a list of Pharmacokinetic Parameters. See: [[Pharmaceutical Drugs]] for more information
* See [[Pharmaceutical Drugs]] for more information about other drugs and disorders.


===Mechanism of Action===
===Mechanism of Action===
Line 17: Line 17:
===Drug Resistance===
===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]]
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]]
</StructureSection>
===See Also===
* The page [[Molecular Playground/HIV Protease Inhibitor]] summarizes the history of AIDS before Ritonavir and the impact of Ritonavir and other [[HIV protease]] inhibitors.


===Pharmacokinetics===
===Pharmacokinetics===
{| class="wikitable" border="1" width="52%" style="text-align:center"
<table style="background: cellspacing="0px" align="" cellpadding="0px" width="42%">  
|-
<tr>
!  colspan="12" align="center"| HIV Protease Inhibitor [[Pharmaceutical_Drugs#Pharmacokinetics_Translated|Pharmacokinetics]]<ref>PMID:20400409</ref><ref>Ferry et al, United States Patent US6147095, Pharmacia & Upjohn Company.</ref><ref>L. Veronese et al. Single-Dose Pharmacokinetics of Amprenavir, a Human Immunodeficiency Virus Type 1 Protease Inhibitor, in Subjects with Normal or Impaired Hepatic  Function. Antimicrob Agents Chemother. 2000 April; 44(4): 821–826.</ref><ref>J. Ford, et al. Intracellular and Plasma Pharmacokinetics of Saquinavir-Ritonavir, Administered at 1,600/100 Milligrams Once Daily in Human Immunodeficiency Virus-Infected Patients. Antimicrob Agents Chemother. 2004 July; 48(7): 2388–2393.</ref><ref>PMID:10620574</ref><ref>PMID:16086644</ref><ref>PMID:19131522</ref><ref>PMID: 10952482</ref><ref>PMID:16338276</ref><ref>PMID:19729375</ref><ref>PMID:12668574</ref><ref>PMID:17255144</ref><ref>PMID:10858338</ref>
<td style="width:100%; vertical-align:top;border-width:0px; border-style:inset">
|-
<div style="height:100%; width: 100%">
! Parameter
{{:HIV Protease Inhibitor Pharmacokinetics}}
! [[Ritonavir]]
</div>
! [[Tipranavir]]
</td>
! [[Indinavir]]
</tr>
! [[Saquinavir]]
</table>
! [[Amprenavir]]
! [[Fosamprenavir]]
! [[Lopinavir]]
! [[Darunavir]]
! [[Atazanavir]]
! [[Nelfinavir]]
|-
! [[Pharmaceutical_Drugs#Tmax|T<sub>max</sub>]] (hr)
! 4.4
! ~3
! 1.5
! 3.7
! .98
! 1.5-4
! 2
! .5
! 2-4
! 3.1
|-
! [[Pharmaceutical_Drugs#Cmax|C<sub>max</sub>]] (ng/ml)
! 13120
! 14600
! 8100
! 2297
! 4901
! 4820
! 11.9
! 2730
! ~4393
! 4701
|-
! [[Pharmaceutical_Drugs#Bioavailability_.28F.29|Bioavailability]] (%)
! --
! --
! 65
! 4
! --
! --
! --
! --
! 68
! 20-80
|-
! [[Pharmaceutical_Drugs#Protein_Binding|Protein Binding]] (%)
! 99
! >99
! 61
! 98
! 90
! 90
! 99
! 95
! 86
! 98
|-
! [[Pharmaceutical_Drugs#Half_Life_.28T1.2F2.29|T<sub>1/2</sub>]] (hr)
! 4.8
! 4.2
! 1.2
! 4.5
! 5.5
! 7.7
! 6.1
! 29.4
! 5.3
! 3.3
|-
! [[Pharmaceutical_Drugs#Area_Under_the_Curve_.28AUC.29|AUC]] (ng/ml/hr)
! 128100
! 46500
! 20900
! 13467
! 11999
! 35000
! 117600
! 4746
! ~26045
! 31906
|-
! [[Pharmaceutical_Drugs#Clearance_.28Cl.29|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)
|}


===References===
===References===

Latest revision as of 18:31, 28 December 2023

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

Ritonavir, better known as Norvir, (1hxw)

Drag the structure with the mouse to rotate

See Also

Pharmacokinetics

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

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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