Trandolapril

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(New page: <applet load="" size="480" color="" frame="true" spin="on" Scene ="Perindopril/Perindoprilat/2" align="right" caption="Perindoprilat, the metabolite of Perindopril, also known as Aceon"...)
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<applet load="" size="480" color="" frame="true" spin="on" Scene ="Perindopril/Perindoprilat/2" align="right" caption="Perindoprilat, the metabolite of Perindopril, also known as Aceon"/>
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<StructureSection load='' size='340' side='right' caption='Trandolaprilat, the metabolite of Trandolapril, also known as Mavik' scene='Trandolapril/Trandolaprilat/1'>
===Better Known as: Mavik===
===Better Known as: Mavik===
* Marketed By: Abbott Labs<br />
* Marketed By: Abbott Labs<br />
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* Date of FDA Approval (Patent Expiration): 1996 (2006)<br />
* Date of FDA Approval (Patent Expiration): 1996 (2006)<br />
* 2006 Sales: $50 Million
* 2006 Sales: $50 Million
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* Why You Should Care: Appears to have been an unsuccessful launch of a new [Angiotensin-Converting Enzyme]] Inhibitor in a market with several established compounds already available.
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* Importance: Appears to have been an unsuccessful launch of a new [[Angiotensin-Converting Enzyme]] Inhibitor in a market with several established compounds already available.
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* The following is a list of Pharmacokinetic Parameters. See: [[Pharmaceutical Drugs]] for more information
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* See [[Pharmaceutical Drugs]] for more information about other drugs and diseases.
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===Mechanism of Action===
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Angiotensin II has been implicated in cardiac, renal and vascular diseases. Bradykinin, a small peptide that counterbalance the effects of Angiotensin II by acting as a strong vasodilator upon binding AT2, is degraded by the same ACE-1 enzyme. Since ACE-1 is the primary producer of Angiotensin II and degrader of Bradykinins, inhibition of ACE-1 has proven an effective treatment for [[Hypertension]].<ref>PMID:17083068</ref> Perindopril is rapidly metabolized into its highly active metabolite Perindoprilat by hepatic enzymes. Perindoprilat binds to the active site of <scene name='Perindopril/Perindoprilat_ace/1'>Angiotensin-Converting Enzyme</scene>, actively inhibiting ACE-1 from binding and converting Angiotensin I into Angiotensin II. ACE-1 <scene name='Perindopril/Perindoprilat_binding/1'>binds Perindoprilat</scene> using residues Gln 265, Lys 495, Tyr 504, His 497, His 337, Tyr 496, Ala 338, Glu 368, His 367, HIs 371, Glu 395 and Asp 399 to tightly affix the inhibitor to the active site of ACE-1.
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===Mechanism of Action===
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Angiotensin II has been implicated in cardiac, renal and vascular diseases. Bradykinin, a small peptide that counterbalance the effects of Angiotensin II by acting as a strong vasodilator upon binding AT2, is degraded by the same ACE-1 enzyme. Since ACE-1 is the primary producer of Angiotensin II and degrader of Bradykinins, inhibition of ACE-1 has proven an effective treatment for [[Hypertension]].<ref>PMID:17083068</ref> Trandolapril is rapidly metabolized into its highly active metabolite Trandolaprilat by hepatic enzymes. Trandolaprilat binds to the active site of <scene name='Trandolapril/Ace/1'>Angiotensin-Converting Enzyme</scene>, preventing ACE-1 from binding and converting Angiotensin I into Angiotensin II. ACE-1 <scene name='Trandolapril/Bound/3'>binds Trandolaprilat</scene> using residues Tyr 496, Glu 368, Glu 395, Ser 339, Ala 338, His 367, His 371, Val 502, His 497, Lys 495, Tyr 504, Gln 265, Asp 399, Phe 441, Phe 511 and a Zinc Ion to tightly affix the inhibitor to the active site of ACE-1.
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</StructureSection>
===Pharmacokinetics===
===Pharmacokinetics===
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{| class="wikitable" border="1" width="50%" style="text-align:center"
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<table style="background: cellspacing="0px" align="" cellpadding="0px" width="42%">
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|-
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<tr>
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! colspan="8" align="center"| ACE-Inhibitor [[Pharmaceutical_Drugs#Pharmacokinetics_Translated|Pharmacokinetics]] Comparison at Equivalent Dosages <ref>PMID: 7867683</ref><ref>DOI: 10.1111/j.1365-2710.2005.00646.x</ref><ref>PMID: 16075412</ref><ref>PMID:7527101</ref>
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<td style="width:100%; vertical-align:top;border-width:0px; border-style:inset">
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|-
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<div style="height:100%; width: 100%">
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! Parameter
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{{:ACE Inhibitor Pharmacokinetics}}
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! [[Captopril]]
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</div>
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! [[Lisinopril]]
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</td>
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! [[Ramipril]]
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</tr>
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! [[Enalapril]]
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</table>
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! [[Benazepril]]
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! [[Perindopril]]
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! [[Trandolapril]]
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|-
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! [[Pharmaceutical_Drugs#Tmax|T<sub>max</sub>]] (hr)
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! .98
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! 6.5
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! .67
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! 1.06
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! .5
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! .75
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! .72
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|-
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! [[Pharmaceutical_Drugs#Cmax|C<sub>max</sub>]] (ng/ml)
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! 1210
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! 79
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! 16.4
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! 314
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! 149
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! 105
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! 1.68
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|-
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! [[Pharmaceutical_Drugs#Bioavailability_.28F.29|Bioavailability]] (%)
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! 72
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! 25
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! 28
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! 60
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! 97
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! 24
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! 10
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|-
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! [[Pharmaceutical_Drugs#Protein_Binding|Protein Binding]] (%)
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! 97
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! 0
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! 73
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! 20
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! 97
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! 20
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! 80
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|-
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! [[Pharmaceutical_Drugs#Half_Life_.28T1.2F2.29|T<sub>1/2</sub>]] (hr)
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! .56
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! 10.1
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! 1.93
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! 1.6
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! 10
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! .9
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! .68
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|-
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! [[Pharmaceutical_Drugs#Area_Under_the_Curve_.28AUC.29|AUC]] (ng/ml/hr)
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! 1673
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! 1016
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! 21.9
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! 450
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! 140
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! 182
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! 1.86
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|-
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! [[Pharmaceutical_Drugs#Inhibitory_Concentration_.28IC50.29|IC<sub>50</sub>]] (nM)
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! 1.1
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! 5.5
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! 5.0
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! 5.4
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! 1.7
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! 2.4
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! 2.5
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|-
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! Dosage (mg)
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! 10
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! 20
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! 5
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! 20
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! 10
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! 4
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! 2
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|-
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! Metabolism
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! Hepatic (CYP2D6)
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! None
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! Hepatic
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! Hepatic (CYP3A4)
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! Hepatic
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! Hepatic
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! Hepatic (CYP2D6 & CYP2C9)
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|}
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==References==
==References==

Current revision

Trandolaprilat, the metabolite of Trandolapril, also known as Mavik

Drag the structure with the mouse to rotate

Pharmacokinetics

ACE-Inhibitor Pharmacokinetics Comparison at Equivalent Dosages
Parameter Captopril Lisinopril Ramipril Enalapril Benazepril Perindopril Trandolapril
Tmax (hr) .98 6.5 .67 1.06 .5 .75 .72
Cmax (ng/ml) 1210 79 16.4 314 149 105 1.68
Bioavailability (%) 72 25 28 60 97 24 10
Protein Binding (%) 97 0 73 20 97 20 80
T1/2 (hr) .56 10.1 1.93 1.6 10 .9 .68
AUC (ng/ml/hr) 1673 1016 21.9 450 140 182 1.86
IC50 (nM) 1.1 5.5 5.0 5.4 1.7 2.4 2.5
Dosage (mg) 10 20 5 20 10 4 2
Metabolism Hepatic (CYP2D6) None Hepatic Hepatic (CYP3A4) Hepatic Hepatic Hepatic (CYP2D6 & CYP2C9)

For Pharmacokinetic Data References, See: References

References

  1. ↑ Ferrario CM. Role of angiotensin II in cardiovascular disease therapeutic implications of more than a century of research. J Renin Angiotensin Aldosterone Syst. 2006 Mar;7(1):3-14. PMID:17083068


Proteopedia Page Contributors and Editors (what is this?)

David Canner, Alexander Berchansky

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