Trandolapril: Difference between revisions

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* 2006 Sales: $50 Million
* 2006 Sales: $50 Million
* Importance: Appears to have been an unsuccessful launch of a new [[Angiotensin-Converting Enzyme]] Inhibitor in a market with several established compounds already available.   
* Importance: Appears to have been an unsuccessful launch of a new [[Angiotensin-Converting Enzyme]] Inhibitor in a market with several established compounds already available.   
* The following is a list of Pharmacokinetic Parameters. See: [[Pharmaceutical Drugs]] for more information
* See [[Pharmaceutical Drugs]] for more information about other drugs and diseases.
 
===Mechanism of Action===
===Mechanism of Action===
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.  
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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{| class="wikitable" border="1" width="50%" style="text-align:center"
{| class="wikitable" border="1" width="50%" style="text-align:center"
|-
|-
!  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>
!  colspan="8" align="center"| ACE-Inhibitor [[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>
|-
|-
! Parameter
! Parameter
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! [[Trandolapril]]
! [[Trandolapril]]
|-
|-
! [[Pharmaceutical_Drugs#Tmax|T<sub>max</sub>]] (hr)  
! [[Pharmacokinetics#Tmax|T<sub>max</sub>]] (hr)  
! .98
! .98
! 6.5
! 6.5
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! .72
! .72
|-
|-
! [[Pharmaceutical_Drugs#Cmax|C<sub>max</sub>]] (ng/ml)  
! [[Pharmacokinetics#Cmax|C<sub>max</sub>]] (ng/ml)  
! 1210
! 1210
! 79
! 79
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! 1.68
! 1.68
|-
|-
! [[Pharmaceutical_Drugs#Bioavailability_.28F.29|Bioavailability]] (%)
! [[Pharmacokinetics#Bioavailability_.28F.29|Bioavailability]] (%)
! 72
! 72
! 25
! 25
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! 10
! 10
|-
|-
! [[Pharmaceutical_Drugs#Protein_Binding|Protein Binding]] (%)
! [[Pharmacokinetics#Protein_Binding|Protein Binding]] (%)
! 97
! 97
! 0
! 0
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! 80
! 80
|-
|-
! [[Pharmaceutical_Drugs#Half_Life_.28T1.2F2.29|T<sub>1/2</sub>]] (hr)
! [[Pharmacokinetics#Half_Life_.28T1.2F2.29|T<sub>1/2</sub>]] (hr)
! .56
! .56
! 10.1
! 10.1
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! .68
! .68
|-
|-
! [[Pharmaceutical_Drugs#Area_Under_the_Curve_.28AUC.29|AUC]] (ng/ml/hr)
! [[Pharmacokinetics#Area_Under_the_Curve_.28AUC.29|AUC]] (ng/ml/hr)
! 1673
! 1673
! 1016
! 1016
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! 1.86
! 1.86
|-
|-
! [[Pharmaceutical_Drugs#Inhibitory_Concentration_.28IC50.29|IC<sub>50</sub>]] (nM)
! [[Pharmacokinetics#Inhibitory_Concentration_.28IC50.29|IC<sub>50</sub>]] (nM)
! 1.1
! 1.1
! 5.5
! 5.5
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