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Nelfinavir: Difference between revisions

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New page: <applet load="" size="480" color="" frame="true" spin="on" Scene ="" align="right" caption="Nelfinavir, better known as Viracept, (1hxw)"/> ===Better Known as: Viracept=== * Markete...
 
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<applet  load="" size="480" color="" frame="true"  spin="on" Scene ="" align="right" caption="Nelfinavir, better known as Viracept, ([[1hxw]])"/>
<StructureSection load='' size='340' side='right' caption='Nelfinavir, better known as Viracept, ([[1ohr]])' scene='Nelfinavir/Nelfinavir_b/2'>
===Better Known as: Viracept===
===Better Known as: Viracept===
* Marketed By: Agouron Pharmaceuticals (now part of Pfizer) & Roche<br />
* Marketed By: Agouron Pharmaceuticals (now part of Pfizer) & Roche<br />
Line 7: Line 7:
* 2004 Sales: $400 Million
* 2004 Sales: $400 Million
* Importance: Soon after its approval, it became the vest selling [[HIV Protease]] inhibitor monotherapy in the world.  
* Importance: Soon after its approval, it became the vest selling [[HIV Protease]] inhibitor monotherapy in the world.  
* 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===
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 <scene name='Ritonavir/Prot/3'>HIV Protease</scene> 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 <scene name='Ritonavir/Cat/1'>two Asp-Thr-Gly conserved sequences</scene>, which contain the <scene name='Ritonavir/Cat/2'>catalytic Asp residues</scene>. These catalytic Asp residues carry out the hydrolytic cleavage of the viral polyproteins. Saquinavir <scene name='Ritonavir/Cat/3'>binds very precisely</scene> 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.<ref>PMID:1799632</ref><ref>PMID:17243183</ref>
When [[HIV]] infects a host, it directs the synthesis of several polyproteins during its maturation process. The maturation of the virus to its infectious form requires that these polyproteins be cleaved to their component proteins by [[HIV Protease]]. The two subunits of <scene name='Nelfinavir/Prot/1'>HIV Protease</scene> 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 <scene name='Nelfinavir/At/1'>two Asp-Thr-Gly conserved sequences</scene>, which contain the <scene name='Nelfinavir/Asp/1'>catalytic Asp residues</scene>. These catalytic Asp residues carry out the hydrolytic cleavage of the viral polyproteins. Nelfinavir <scene name='Nelfinavir/Nelfinavir_b/1'>binds very precisely</scene> 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.<ref>PMID:1799632</ref><ref>PMID:17243183</ref>
 
 
Despite its ability to inhibit HIV Protease, Ritonavir is primarily used in combination therapies to inhibit the metabolizing enzyme, <scene name='Ritonavir/Ritonavir_cyp/2'>cytochrome P4503A4</scene> (CYP3A4). Ritonair binds with <scene name='Ritonavir/Ritonavir_c/2'>high affinity to CYP3A4</scene>, 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 [[Pharmaceutical_Drugs#Treatments|antiviral medications]].<ref>PMID: 20937904</ref>


===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>
===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===

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

David Canner, Alexander Berchansky
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